WO2012013850A2 - Compound for treating neurodegenerative diseases, cognitive deficiencies and/or dementia - Google Patents

Abstract

The invention relates to the use of a gemifloxacin compound for the treatment of neurodegenerative diseases, mild cognitive impairment, cognitive deficiencies, dementia, diseases associated with ageing and pathological processes associated with age and progeria and, in particular, Alzheimer's disease, owing to the discovery of novel properties intrinsic to said compound.

Description

 COMPOSITE TO TREAT NEURODEGENERATIVE DISEASES, COGNITIVE DEFICITS AND / OR DEMENCIES

FIELD OF THE INVENTION The invention relates to the use of the gemifloxacin compound

(7 ⁴ - (Z) - (0-methyloxy ma) d acid (±) -7- [3- (aminomethyl) -4-oxo-1-pyrrolidinyl] -1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid) for the treatment of neurodegenerative diseases, cognitive deficits, dementias and especially Alzheimer's disease, due to the discovery of new intrinsic properties to this compound.

BACKGROUND OF THE INVENTION

 The high incidence of neurodegenerative diseases and diseases associated with aging such as cognitive deficits or dementias, is a major problem worldwide. Therefore it is necessary to search for neuroprotective compounds that prevent or mitigate these diseases. Of all of them, Alzheimer's disease (AD) is the most prevalent, estimating that in 2040, 81 million people will suffer from this disease (Blennow et al., Lancet 2006; 368: 387-403). In Spain alone it is estimated that more than half a million people currently suffer from AD. The costs associated with this disease are proportionally high, and it is estimated that the total cost derived from the care of Alzheimer's patients is € 81,000 and € 22,000 million in the United States and the United Kingdom, respectively. Currently there are no efficient drugs that prevent or prevent this disease, so the search and validation of new neuroprotective compounds that prevent neuronal damage is a necessity.

One of the previous stages associated with AD and other dementias is mild cognitive impairment or MCI (from English Mild Cognitive Impairment), also known as incipient dementia or isolated memory impairment. MCI is recognized as a risk factor for AD, and affects about 30 million people worldwide. The MCI is considered as a previous step to the EA, where between 10 and 15% of individuals with MCI progress to EA each year (Grundman et al. Arch. Neurol 2004; 61 [1]: 59-66). Despite the significant prevalence of MCI and the high risk of patients to progress to dementias, there is currently no treatment or therapy for this clinical entity, which recommends the use of antioxidants or drugs against AD for treatment. of the MCI. Current therapeutic options against AD are based on the inhibition of acetylcholinesterase with drugs such as donepezil, galantamine or rivastigmine, or on the ability of memantine to antagonize a glutamate receptor, NMDA (N-methyl acid). D-aspartic). However, it has been shown that the use of rivastigmine does not stop or slow the progression of MCI or AD (Feldman et al. Lancet Neurol 2007; 6 [6]: 501-12), while the use of donepezil only shows Discrete short-term benefits, but with the disadvantage of presenting significant side effects (Birks and Flicker, Cochrane Datábase Syst Rev 2006; 3: CD006104). Thus, there are currently no drugs for the treatment of MCI, and current anti-AD drugs offer few benefits to patients, which temporarily delay (in the best case one year), some symptoms of the ailment, But they don't prevent its evolution. Due to the lack of success of these drugs, new lines of research have been opened, and among them, the drug repositioning strategy is based on the discovery of new indications for medications that are well being used in the market for other indications. , or have passed Phase I (studies of first administration and evaluation of human safety). The repositioning strategy has advantages such as the knowledge of clinical pharmacology, the possibility of carrying out rapid concept tests, the reduction of toxicological risk and the knowledge of administration and galenic development.

On the other hand, in WO 2009/149149, the use of one or more antibiotics, alone or in combination with exogenous microflora or with one or more probiotic compounds, is described in order to modify the population of the microflora to provide an autoimmune regulatory effect and thus make possible the treatment of autoimmune diseases

SUMMARY OF THE INVENTION

The inventors have now surprisingly found that gemifloxacin, commonly used as an antibiotic, has neuroprotective properties. Gemifloxacin is a fourth generation compound of the fluoroquinolone family, which are bactericidal antimicrobials that inhibit bacterial DNA synthesis by blocking subunit A of DNA gyrase (topoisomerase II). Fluoroquinolones have a high oral bioavailability, an excretion mainly by the renal route, and in general they are well tolerated, although some of them have manifested side effects in the central nervous system such as encephalopathies, seizures, confusion or psychosis. The inventors have revealed the neuroprotective activity of gemifloxacin by studying the protection of neuronal death caused by endoplasmic reticulum stress (Example 1), by disorganization of the cytoskeleton (Example 2) or by mitochondrial damage (such as inhibition of succinate dehydrogenase) (Huntington's model) in human cell lines of inertic origin (Example 3). Neuroprotective activity has been confirmed by studying the protection of neuronal death caused by apoptosis in human cell lines of cholinergic origin (Example 4). In addition, gemifloxacin has the ability to inhibit acetylcholinesterase (AChE) (Alzheimer's model) both in vitro and in vivo (Example 5). Finally, it has been determined that gemifloxacin crosses the blood-brain barrier efficiently (Example 6), thus making it potentially useful for the treatment of neurodegenerative diseases, cognitive deficits or dementias, and especially for Alzheimer's and Huntington's diseases. These examples show the potential use of gemifloxacin in the prevention and / or treatment of neuronal death associated with neurodegenerative diseases (eg, Alzheimer's disease, mild cognitive impairment, Huntington, Parkinson's, multiple sclerosis, amyotrophic lateral sclerosis, Creutzfeldt-Jakob, cognitive and / or psychomotor deficits, ataxias, dementias, cerebrovascular diseases, Alexander's disease, etc.), cognitive deficits, dementias, diseases associated with aging, pathological processes associated with age and progeria.

 The results obtained can be extrapolated for prophylactic or therapeutic purposes for application to the population at risk. Also, because this compound is commonly used as an antibiotic, pharmacovigilance studies have shown that it has a relatively low toxicity profile, so its use as a neuroprotective drug is very appropriate and does not require complex clinical trials as occurs with others. Candidates for drugs whose toxicity and safety are unknown.

 Therefore, in one aspect, the invention relates to the use of gemifloxacin in the preparation of a pharmaceutical composition for the prevention and / or treatment of neurodegenerative diseases, mild cognitive impairment, cognitive deficits, dementias or diseases associated with aging, processes pathological associated with age and progeria.

 In another aspect, the invention relates to the use of a pharmaceutical composition of gemifloxacin for the prevention and / or treatment of neurodegenerative diseases, mild cognitive impairment, cognitive deficits, dementias or diseases associated with aging, pathological processes associated with age and progeria takes place by neuroprotection, in particular by direct inhibition of neuronal death.

 In a further aspect, the invention relates to the use of a pharmaceutical composition of gemifloxacin for the prevention and / or treatment of neurodegenerative diseases, mild cognitive impairment, cognitive deficits, dementias or diseases associated with aging, pathological processes associated with age and progeria, by modulating the neurotransmitter acetylcholine.

Finally, the invention relates to a method for the prevention and / or treatment of neurodegenerative diseases, cognitive deficits, dementias or diseases associated with aging, in a subject in need of treatment, which comprises administering to said subject a therapeutically efficient amount of gemifloxacin, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 is a bar graph depicting the protective effect of gemifloxacin on neuronal death caused by tunicamycin (TM). The figure shows the percentage of cell death (taking 100% of that produced by TM) of the cultures treated with 23 μΜ TM and gemifloxacin at different concentrations, representing the means ± SD of 3 independent experiments per triplicate. ^* Significant difference with respect to treatments with TM alone, according to the Student test (p <0.05).

Figure 2 is a bar graph depicting the protective effect of gemifloxacin on neuronal death caused by okadaic acid (AO). The figure shows the percentage of cell death (taking 100% of that produced by AO) of the cultures treated with 20 nM AO and gemifloxacin at different concentrations, representing the means ± SD of 3 independent experiments per triplicate. ^* Significant difference compared to treatments with AO alone, according to the Student test (p <0.05).

 Figure 3 is a bar graph depicting the protective effect of gemifloxacin on neuronal death caused by 3-nitropropionic acid (3-NP). The figure shows the percentage of cell death (taking 100% of that produced by 3-NP) of the cultures treated with 30 μΜ 3-NP and gemifloxacin at different concentrations, representing the means ± SD of 3 independent experiments in triplicate.

Figure 4 is a bar graph depicting the protective effect of gemifloxacin on neuronal death caused by camptothecin (CPT). The figure shows the percentage of cell death (taking 100% of that produced by CPT) of the cultures treated with 20 nM CPT and gemifloxacin at different concentrations, representing the means ± SD of 3 experiments triplicate independent. ^* Significant difference with respect to treatments with CPT alone, according to the Student test (p <0.05).

Figure 5 is a bar graph depicting the neuroprotective effect of gemifloxacin [encoded in the figure as GFX] (compared to the specific cashase inhibitor Z-VAD-fmk) of caspase activation 3/7 by camptothecin (CPT). The figure shows the percentage of inhibition of caspase activity 3/7 of the cultures treated with 50 μΜ CPT and gemifloxacin at different concentrations and Z-VAD-fmk (in the presence or absence of CPT), representing the means ± SD of 2 experiments triplicate independent. ^* Significant difference with respect to treatments with CPT alone, according to the Student test (p <0.05).

Figure 6 is a bar graph depicting the neuroprotective effect of gemifloxacin [encoded in the figure as GFX] (in comparison to the specific cashase inhibitor Z-VAD-fmk) of camptothecin apoptosis (CPT) and determined by flow cytometry. The figure shows the percentage of apoptotic cells determined by DNA fragmentation (taking 100% activity produced by CPT) of cultures treated with 50 μ con CPT and gemifloxacin at different concentrations and Z-VAD-fmk (in the presence or absence of CPT), representing the means ± SD of 2 independent experiments in triplicate. ^* Significant difference with respect to treatments with CPT alone, according to the Student test (p <0.05).

Figure 7 is a bar graph depicting the in vitro inhibitory effect on gemifloxacin acetylcholinesterase (AChE) (as compared to the specific inhibitor of BW284c51). The figure shows the percentage of AChE activity and its modification by gemifloxacin at different concentrations and BW284c51, represents the mean ± SD of 2 independent experiments in triplicate. ^* Significant difference with respect to the control (without treatment), according to the Student test (p <0.05).

Figure 8 is a bar graph depicting the inhibitory effect in vivo on gemifloxacin acetylcholinesterase (AChE) (as compared to the specific inhibitor of BW284c51). The figure shows the percentage of AChE cellular activity normalized by the amount of protein and its inhibition by gemifloxacin at different concentrations and BW284c51, representing the means ± SD of 2 independent experiments in triplicate. ^* Significant difference with respect to the control (without treatment), according to the Student test (p <0.05).

Figure 9 is an XY scatter plot depicting the passage of blood-brain barrier by passive diffusion of gemifloxacin compared to a drug that crosses the barrier easily (verapamil) and another that does not cross the barrier (theophylline). The percentage of hematoencephalic barrier passage of the compounds is represented on the X axis, and the effective permeability parameter (P _e ) of the compounds is represented on the Y axis.

 Figure 10 is an XY scatter plot depicting the blood-brain barrier passage of gemifloxacin [encoded in the figure as GFX] in adult zebrafish (means ± SEM). The fish were administered with 1 000 mg / kg of gemifloxacin in the water and the amount of compound was determined in the animals' brains after 15 min, 30 min, 1 h, 4 h and 24 h post-treatment by UPLC / MS. On the X axis the post-treatment time of gemifloxacin is represented, and on the Y axis the amount of gemifloxacin in the brain (weight / weight) is represented.

DETAILED DESCRIPTION OF THE INVENTION

 Definitions

 To facilitate the understanding of the invention object of this patent application, the meaning of some terms and expressions used in the context of the invention is set forth below.

A "neurotoxic substance" as used herein is chemical substances that produce functional, structural and biochemical alterations of the central nervous system. These adverse effects involve changes that cause deregulation or alteration of the nervous system. The nature of such change may be neurochemical, morphological, or behaviorally related and may manifest itself temporarily or permanently. The term "neurodegenerative disease", as used herein, includes diseases that result from degeneration or deterioration of nerve tissue, in particular neurons, which leads, over time, to dysfunction or disability; The term degeneration includes loss of cell viability, loss of cell function and / or loss of the number of cells (n eu ronas and others). Illustrative, non-limiting examples of neurodegenerative diseases include Alzheimer's disease, mild cognitive impairment, Huntingon's disease, Parkinson's disease, Creutzfeldt-Jakob disease, Alexander's disease, cognitive and / or psychomotor deficits, ataxias, dementias, cerebrovascular diseases, Amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), etc. In a particular embodiment, said neurodegenerative disease is a disease related to neuronal death caused by a neurotoxic substance, for example, a substance that produces endoplasmic reticulum stress, apoptosis, cytoskeleton disorganization, degeneration of the basal ganglia or mitochondrial damage.

 The terms "neuroprotection" and "neuroprotector", as used herein, refer to the attenuation of the effects of neuronal degeneration or death by any known mechanism or by knowing for example, necrosis, apoptosis, autophagy, excitotoxicity, damage oxidative, mitochondrial damage, endoplasmic reticulum damage, byproduct deposition, loss of cellular architecture, etc., or the disappearance of the effects of neuronal degeneration or death by any known mechanism or by knowing for example, necrosis, apoptosis, autophagy, excitotoxicity, oxidative damage, mitochondrial damage, endoplasmic reticulum damage, byproduct deposition, loss of cellular architecture, etc., or the decrease or disappearance of its side effects.

The term "subject", as used herein, refers to a member of a mammalian species, and includes, but is not limited to, pets, primates and humans; preferably, the subject is a human being, male or female, of any age or race. In a particular embodiment, said subject is a mammal who suffers, or is susceptible to disease. neurodegenerative, such as a chronic neurodegenerative disease or a disease associated with aging.

 The term "salt" should be understood as meaning any form of gemifloxacin in which the compound assumes an ionic form, or is charged and is coupled with a counterion (a cation or anion) or is in solution. This should also be understood as complexes of the active compound with other molecules and ions, and in particular complexes that are complexed through ionic interactions.

 The term "solvate" according to this invention should be understood as meaning any form of the gemifloxacin compound that has another molecule (more likely a solvent) attached through a non-covalent bond.

 The term "prodrug" or "prodrug" is used in its broadest sense and encompasses those derivatives that are converted in vivo into the compounds of the invention. Such derivatives will readily occur to those skilled in the art, and include, depending on the functional groups present in the molecule. Examples of well known methods for producing a prodrug of a given acting compound are known to those skilled in the art and can be found, for example, in Krogsgaard-Larsen et al., "Textbook of Drugdesign and Discovery" Taylor & Francis (April 2002). Particularly favorable derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (for example, allowing a compound administered orally to be more easily absorbed in the blood) or those that increase the administration of the original compound a biological compartment (for example, the brain or lymphatic system) in relation to the original species.

The term "pharmaceutically acceptable" refers to molecular compositions and entities that are physiologically tolerable and do not normally produce allergic reactions or similar unfavorable reactions such as gastric disorders, dizziness, and reactions of the same style, when administered in humans or animals. Preferably, the term "pharmaceutically acceptable" means that it is approved by an agency. regulatory, or that is included in a pharmacopoeia for use in animals, and particularly in humans.

New therapeutic uses of qemifloxacin

 In one aspect, the invention relates to the use of gemifloxacin of formula (I), salts, prodrugs and / or solvates thereof, in the elaboration of a pharmaceutical composition for the prevention and / or treatment of death. eu rona l, in particular that associated with neurodegenerative diseases, mild cognitive impairment, cognitive deficits, dementias, diseases associated with aging and / or pathological processes associated with age and progeria.

 (l)

The results of the research carried out by the inventors demonstrate that the prevention and / or treatment of neurodegenerative diseases, mild cognitive impairment, cognitive deficits, dementias, diseases associated with aging and / or pathological processes associated with age and progeria with the gemifloxacin compound takes place, at least partially, by neuroprotection, in particular by direct inhibition of neuronal death, that is, by inhibiting the death of neuronal cells of the nervous system once said compound has crossed the blood brain barrier (BHE). Therefore, this mechanism of action would take place without the involvement of the immune system. Numerous trials carried out by the inventors have revealed both the neuroprotective effect of gemifloxacin against the action of different neurotoxic substances, and its antiapoptotic effect in cholinergic neurons of human origin.

 The neuroprotective effect of gemifloxacin against the action of a substance causing endoplasmic reticulum stress (tunicamycin) in human cholinergic cells is described in Example 1. In this example, it was observed that gemifloxacin is able to quantitatively and significantly reduce the neural death caused by endoplasmic reticulum stress, which demonstrates the neuroprotective capacity of said compound (Figure 1).

 In order to better define the neuroprotective effect of the compound, the inventors analyzed in Example 2 in more detail the neurodegenerative process by analyzing the neuronal death caused by the action of okadaic acid (AO), which is a causative substance cell death due to disorganization of the cytoskeleton. The AO is used to pharmacologically model one of the histopathological marks observed in the brains of Alzheimer's patients, such as neurofibrillary tangles or tangles, a consequence of the hyperphosphorylation of the Tau protein. In this example, it was stated that gemifloxacin is able to quantitatively and significantly reduce neuronal death caused by disorganization of the cytoskeleton, which demonstrates the neuroprotective capacity of said compound (Figure 2).

In order to better define the neuroprotective effect of the compound, the inventors analyzed in Example 3 in more detail the neurodegenerative process by analyzing neuronal death caused by treatment with 3-nitropropionic acid (3-NP) , which is a mitochondrial toxin that interferes with the syntheses of ATP, in which the enzyme is succinate dehydrogenase, which causes oxidative stress and cell death. 3-NP is used to pharmacologically model the neurodegeneration characteristic of Huntington's disease. In this example, it was observed that gemifloxacin is able to quantitatively reduce neuronal death caused by damage mitochondrial, which shows the neuroprotective capacity of said compound (Figure 3).

 In order to better define the neuroprotective effect of the compound, the inventors analyzed in Example 4 in more detail the neurodegenerative process by analyzing the neuronal death caused by the action of a substance causing apoptosis (camptothecin [CPT] ), determining that gemifloxacin is able to quantitatively and significantly reduce neuronal death caused by apoptosis, which demonstrates the neuroprotective capacity of said compound (Figure 4). Likewise, in order to better define the neuroprotective effect of this co m pu this, the inventors analyzed the neurodegenerative process with more analysis by analyzing the activity of caspase 3/7 determining that gemifloxacin It is able to quantitatively and significantly reduce the activation of caspase 3/7, compared to a specific inhibitor of neuronal death by apoptosis, Z-VAD-fmk, which shows the neuroprotective capacity of said compound ( Figure 5). Also, in order to better define the neuroprotective effect of said compound, the inventors analyzed in more detail the neurodegenerative process by means of flow cytometry of neuronal death caused by apoptosis and its inhibition by gemifloxacin, compared with a specific inhibitor of Neural death by apoptosis, Z-VAD-fmk, determining that gemifloxacin is able to quantitatively and significantly inhibit neuronal death caused by apoptosis (Figure 6).

In order to better define the neuroprotective effect of the compound, the inventors analyzed in Example 5 the ability to inhibit the enzyme acetylcholinesterase (AChE) in vitro, since this enzyme degrades the neurotransmitter acetylcholine (ACh), forming choline and acetate and preventing ACh activity in the nervous synapse, which has been related to, among others, Alzheimer's disease (AD). In this example, it was observed that gemifloxacin is able to inhibit AChE in vitro, compared to a specific AChE inhibitor, which shows the neuroprotective capacity of said compound (Figure 7). Also, with the objective of to better define the inhibitory effect of gemifloxacin on AChE, the inventors analyzed in more detail the inhibition through in vivo studies using human neurons, observing that gemifloxacin is capable of inhibiting AChE in vivo, compared with a specific AChE inhibitor, which shows the neuroprotective capacity of said compound (Figure 8). Therefore, in another aspect of the invention, gemifloxacin or a pharmaceutical formulation thereof is claimed for use in the modulation of the neurotransm isor acetilcol ina and for the prevention and / or treatment of diseases related to the modulation of the neurotransmitter acetylcholine.

 In order to better define the neuroprotective effect of the compound, the inventors analyzed in Example 6 the ability to cross the blood-brain barrier (BHE) of gemifloxacin. In this example, it was observed that gemifloxacin is able to pass through BHE by passive diffusion with greater efficiency than a known compound (theophylline) that does not cross the barrier, and close to a known compound that does cross it (verapamil), which shows the therapeutic utility of said compound in neuroprotection (Figure 9). Additionally, the researchers determined that gemifloxacin is capable of crossing BH E in an vertebrate animal model such as zebrafish, confirming its therapeutic utility (Figure 10).

 It may be the case that neurodegenerative diseases are due to autoimmune processes such as amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). The pharmaceutical composition provided by this invention, comprising gemifloxacin, is used for the prevention and / or treatment of amyotrophic lateral sclerosis and multiple sclerosis, such that the active substance gemifloxacin acts by neuroprotection, in particular by direct inhibition. of neuronal death.

For its ad mini stration in the prevention and / or treatment of neurodegenerative diseases, cognitive deficits, dementias or diseases associated with aging, gemifloxacin will be formulated in a pharmaceutical composition, in a therapeutically effective amount, together with one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical composition provided by this invention may contain gemifloxacin or one or more other drugs together with one or more pharmaceutically acceptable carriers or excipients. In a particular embodiment, the pharmaceutical position comprises only gemifloxacin. Said pharmaceutical composition is useful for the treatment of neurodegenerative diseases, cognitive deficits, dementias or diseases associated with aging.

Pharmaceutical compositions comprising gemifloxacin, provided by this invention, may be formulated in any pharmaceutical form of administration suitable for administration by the route of administration chosen. By way of illustration, not limitation, the pharmaceutical compositions provided by this invention may be formulated in a solid pharmaceutical form for oral administration (eg, granules, tablets, capsules, etc.), in a liquid pharmaceutical form for oral administration. (eg, solutions, suspensions, emulsions, etc.), in a pharmaceutical form for parenteral administration (eg, solutions, suspensions, emulsions, etc.). For this, in each case, the pharmaceutically acceptable carriers and excipients appropriate for the chosen pharmaceutical form and route of administration will be chosen, for example, binders, diluents, disintegrants, lubricants, huctants, etc. , for the formation of solid farm administration forms, and buffers, surfactants, etc., for the formulation of liquid administration pharmaceutical forms. Such vehicles and excipients must be pharmaceutically acceptable and pharmacologically tolerable and must be able to be combined with other components of the formulation without exerting any adverse effect on the treated subject. Information on said vehicles and excipients, as well as on said pharmaceutical forms of administration of said active ingredient can be found in galenic pharmacy treaties. A review of the different pharmaceutical forms of drug administration, in general, and their preparation procedures can be found in the book "Treaty of Farmacia Galenica ", C. Fauli i Trillo, 1st Edition, 1993, Luzan 5, SA de Ediciones.

 The pharmaceutical composition provided by this invention comprises at least gemifloxacin in a therapeutically efficient amount. In the sense used in this description, the term "therapeutically efficient amount" refers to the amount of drug calculated to produce the desired effect. The dose of drug to be administered to a subject may vary within a wide range depending on numerous factors, including the characteristics of the drug used, eg, its activity and biological half-life, the concentration of the drug in the composition. pharmaceutical, the clinical situation of the subject, the severity of the pathology, the pharmaceutical form of administration chosen, etc. The pharmaceutical composition provided by this invention can be administered one or more times a day for preventive or therapeutic purposes or with other administration guidelines, not necessarily daily but also on a timely, weekly basis, etc. In a particular embodiment, the dose of active ingredient administered to a subject in need of treatment for the treatment and / or prevention of the aforementioned conditions is in the range of 0.1 to 20 mg / kg of body weight, usually between 0.2 and 15 mg / kg body weight and preferably between 1 and 13 mg / kg body weight.

 In one aspect the invention relates to a method for the prevention or treatment of neurodegenerative diseases, cognitive deficits, dementias or diseases associated with aging, in a subject in need of treatment, which comprises the administration to said subject of a pharmaceutical composition. comprising a therapeutically efficient amount of gemifloxacin, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof. In a preferred aspect, this method of prevention or treatment acts by neuroprotection, in particular by direct inhibition of neuronal death.

Another aspect of the invention concerns a method in which the pharmaceutical composition provided by this invention, if desired, can be used together with other drugs, for example, drugs useful in the treatment of neurodegenerative diseases, cognitive deficits, dementias or diseases associated with aging, in order to increase the efficiency of the pharmaceutical composition provided by this invention, thereby generating a combination therapy. Such additional drugs may be part of the same pharmaceutical composition or, alternatively, may be provided as a separate pharmaceutical composition for administration at the same time (simultaneous administration) as the pharmaceutical composition provided by this invention or at different times (sequential administration) with respect to the administration of the pharmaceutical composition provided by this invention. By way of illustration, not limitation, examples of additional drugs that may be part of the same therapy or pharmaceutical composition with gemifloxacin are: drugs for the treatment of Alzheimer's (tacrine, rivastigm ina, memantine, donepezil, galantam ina. ..), from parkinson's (carbidopa, levodopa, bromocriptine, pramipexole, ropinirole, amantadine, rasagiline ...), antipsychotics such as haloperidol, antidepressants such as amitriptyline, anti-inflammatory agents such as lorazepam, anti-inflammatory agents such as aspirin, dietary supplements Vitamins E, C, B, folate or Ginkgo biloba extract or drugs against the rest of neurodegeneratives indicated in the patent.

 In another aspect, the invention relates to gemifloxacin for the treatment and / or prevention of neurodegenerative diseases, cognitive deficits, dementias or diseases associated with aging. The characteristics of the drug as well as those of said diseases have already been mentioned previously.

In another aspect, the invention relates to a method for the prevention and / or treatment of neurodegenerative diseases, cognitive deficits, dementias or diseases associated with aging, which comprises administering to a subject in need of treatment a therapeutically efficient amount of gemifloxacin. or of a pharmaceutical composition provided by this invention which includes gemifloxacin. The characteristics of the drug as well as those Pharmaceutical diseases and compositions comprising a drug have already been mentioned previously.

 The following Examples serve to illustrate the invention and should not be considered in a limiting sense thereof.

EXAMPLE 1

 Protective effect of gemifloxacin on neuronal death induced by endoplasmic reticulum stress

 The assay was performed on cells in SK-N-MC human neuroblastoma culture from "American Type Culture Collection (ATCC)". In all cases, strict sterility standards were followed and handling was carried out in class II biological safety cabins that follow the European standard EN 12469. The cells were kept in the culture medium "Minimun Essential Medium Eagle "supplemented with 1 mM sodium pyruvate, 2 mM L-glutamine, 0.1 mM non-essential amino acids, 0.05 mg / ml gentamicin and 10% fetal bovine serum.

 The inhibition produced by gemifloxacin mesylate from cell death caused by tunicamycin (TM) treatment that causes endoplasmic reticulum stress was analyzed. TM is an inhibitor of protein N-glycosylation, which causes the abnormal folding of proteins in the endoplasmic reticulum, which means that these proteins accumulate and produce endoplasmic reticulum stress that leads to cell death.

These cells, in a pass not exceeding 15, were seeded on 96-well plates treated for adherent cells with a cell concentration of 5x1 0 ⁴ cells / well; 3 wells of the plate were seeded for each test condition.

 After 24 h of incubation of the cells at 37 ° C and 5% CO2, cell treatments were carried out with 100 μΙ of total volume for the following conditions:

 - Control: culture medium (medium)

- Tunicamycin (TM): medium with tunicamycin 23 μΜ, which causes the death of 50% of the cells. - TM plus gemifloxacin mesylate: medium with TM (23 μΜ) plus gemifloxacin mesylate at 1, 4, 10, 40 or 100 μΜ.

The cells were incubated (at 37 ° C and 5% CO ₂ ) with these treatments for 22 h, after which the WST-1 reagent was added. The WST-1 test is based on the measurement of metabolic activity. The cellular damage causes the loss of the ability of the cells to obtain the energy necessary to maintain their metabolic functions and cell growth, so that metabolically active (living) cells reduce the salt of tetrazol iu ma formazan through the succinate system -tetrazolium reductase (from the mitochondrial respiratory chain). The formazan formed can be detected colorimetrically, since it has an absorbance of 440nm. At 2 hours after the reagent was added, the reading was done on a plate reader at 440 nm.

 The results obtained are shown, as shown in Figure 1, as the percentage of cell death for each treatment referred to the death produced by TM. Death protection was observed at 4, 10 and 40 μΜ of gemifloxacin mesylate, reaching approximately 50% at 40 μΜ. From these results it is concluded that gemifloxacin shows a protective effect of the death of human cells of neuronal origin caused by endoplasmic reticulum stress.

EXAMPLE 2

 Protective effect of gemifloxacin on neuronal death induced by okadaic acid

The assay was performed on cells in SK-N-MC human neuroblastoma culture from "American Type Culture Collection (ATCC)". In all cases, strict sterility standards were followed and handling was carried out in class II biological safety cabins that follow the European standard EN 12469. The cells were kept in the culture medium "Minimun Essential Medium Eagle" supplemented with pyruvate. 1 mM sodium, 2 mM L-glutamine, 0.1 mM non-essential amino acids, 0.05 mg / ml gentamicin and 10% fetal bovine serum. The inhibition produced by gemifloxacin mesylate from cell death caused by treatment with okadaic acid (AO) was analyzed. The AO is an inhibitor of protein phosphatase 1 (PP1) and causes cell death by disorganization of the cytoskeleton. The AO is one of the histopathological marks observed in the brains of Alzheimer patients, such as neurofibrillary tangles or tangles, as a result of hyperiosphorylation of the Tau protein.

These cells, in a pass not exceeding 15, were seeded on 96-well plates treated for adherent cells with a cell concentration of 5x1 0 ⁴ cells / well; 3 wells of the plate were seeded for each test condition.

 After 24 h of incubation of the cells at 37 ° C and 5% CO2, cell treatments were carried out with 100 μΙ of total volume for the following conditions:

 - Control: culture medium (medium)

 - Okadaic Acid (AO): medium with 20 nM AO, which causes the death of 50% of the cells.

 - AO plus gemifloxacin mesylate: medium with AO (20 nM) plus gemifloxacin mesylate at 1, 4, 10, 40 or 100 μΜ.

 The cells were incubated (at 37 ° C and 5% CO2) with these treatments for 22 h, after which the WST-1 reagent was added. The WST-1 test is based on the measurement of metabolic activity. The cellular damage causes the loss of the ability of the cells to obtain the energy necessary to maintain their metabolic functions and cell growth, so that metabolically active (living) cells reduce the salt of tetrazolium to formazan through the succinate-tetrazolium system reductase (from the m itochondrial respiratory chain). The formazan formed can be detected colorimetrically, since it has an absorbance of 440nm. At 2 hours after the reagent was added, the reading was carried out on a plate reader at 440 nm.

The results obtained are shown, as shown in Figure 2, as the percentage of cell death for each treatment referred to the death produced by AO. Death protection was observed at 4, 10 and 40 μΜ of gemifloxacin mesylate, reaching 57% at 10 μΜ. From these results it is concluded that gemifloxacin shows a protective effect of the death of human cells of neuronal origin caused by disorganization of the cytoskeleton.

EXAMPLE 3

 Protective effect of gemifloxacin on neuronal death induced by

 3-nitropropionic

 The assay was performed on cells in SK-N-MC human neuroblastoma culture from "American Type Culture Collection (ATCC)". In all cases, strict sterility standards were followed and handling was carried out in class II biological safety cabins that follow the European standard EN 12469. The cells were kept in the culture medium "Minimun Essential Méd ium Eagle "(MEM) supplemented with 1 mM sodium pyruvate, 2 mM L-glutamine, 0.1 mM non-essential amino acids, 0.05 mg / ml gentamicin and 10% fetal bovine serum.

 The inhibition produced by gemifloxacin mesylate from cell death caused by treatment with 3-nitropropionic acid (3-NP) was analyzed. 3-NP is a mitochondrial toxin that interferes with the synthesis of ATP, since it is an inhibitor of the enzyme succinate dehydrogenase, producing oxidative stress and cell death. In mammals, 3-NP causes degeneration of the basal ganglia and movement functions such as dystonia, chorea and hypokinesia, mimicking some aspects of Huntington's disease such as neuroanatomic, physiological and chemical changes.

These cells, in a pass not exceeding 15, were seeded on 96-well plates treated for adherent cells with a cell concentration of 5x1 0 ⁴ cells / well; 3 wells of the plate were seeded for each test condition.

 After 24 h of incubation of the cells at 37 ° C and 5% CO2, cell treatments were carried out with 100 μΙ of total volume for the following conditions:

- Control: culture medium (medium) - 3-Nitropropionic (3-NP): medium with 3-NP 30 μΜ, which causes the death of 50% of the cells.

 - 3-NP plus gemifloxacin mesylate: medium with 3-NP (30 μΜ) plus gemifloxacin mesylate at 1, 4, 10 or 40 μΜ.

The cells were incubated (at 37 ° C and 5% CO ₂ ) with these treatments for 22 h, after which the WST-1 reagent was added. The WST-1 test is based on the measurement of metabolic activity. The cellular damage causes the loss of the ability of the cells to obtain the energy necessary to maintain their metabolic functions and cell growth, so that metabolically active (living) cells reduce the salt of tetrazolium to formazan through the succinate-tetrazolium system reductase (from the m itochondrial respiratory chain). The formed formazan can be detected colorimetrically, since it has an absorbance of 440nm. At 2 hours after the reagent was added, the reading was done on a plate reader at 440 nm.

 The results obtained are shown, as shown in Figure 3, as the percentage of cell death for each treatment referred to the death produced by 3-N P. Protection of death was observed at 1 0 μΜ of gemifloxacin mesylate, reaching 40% at 1 0 μΜ. From these results it is concluded that gemifloxacin shows a protective effect of the death of human cells of neuronal origin caused by mitochondrial damage.

EXAMPLE 4

 Protective effect of gemifloxacin on neuronal death induced by apoptosis

The tests were performed on cells in SK-N-MC human neuroblastoma culture from "American Type Culture Collection (ATCC)". In all cases, strict sterility standards were followed and handling was carried out in class II biological safety cabins that follow the European standard EN 12469. The cells were kept in the culture medium "Minimun Essential Medium Eagle" ( MEM) supplemented with 1 mM sodium pyruvate, 2 mM L-glutamine, 0.1 mM non-essential amino acids, 0.05 mg / ml gentamicin and 10% fetal bovine serum. (i) Protection of death by camptothecin:

 The inhibition produced by gemifloxacin mesylate from cell death caused by camptothecin (CPT) treatment (Sigma) was analyzed. CPT is a cytotoxic alkaloid qu inol that has the DNA topoisomerase I enzyme, so it causes damage to the DNA that leads to apoptosis.

SK-N-MC cells, in pass not exceeding 1 5, were seeded on 96 well plates treated for adherent cells with a cell concentration of 5x10 ⁴ cells / well; 3 wells of the plate were seeded for each test condition.

After 24 h of incubation of the cells at 37 ° C and 5% CO ₂ , cell treatments were carried out with 100 μΙ of total volume for the following conditions:

 - Control: culture medium (medium)

 - Camptotecina (CPT): medium with 20 nM CPT, which causes the death of 50% of the cells.

 - CPT plus gemifloxacin mesylate: medium with CPT (20 nM) plus gemifloxacin mesylate at 1, 4, 10, 40 or 100 μΜ.

The cells were incubated (at 37 ° C and 5% CO ₂ ) with these treatments for 22 h, after which the WST-1 reagent was added. The WST-1 test is based on the measurement of metabolic activity. The cellular damage causes the loss of the ability of the cells to obtain the energy necessary to maintain their metabolic functions and cell growth, so that metabolically active (living) cells reduce the salt of tetrazolium to formazan through the succinate-tetrazolium system reductase (from the respiratory chain m itocond rial). The formed formazan can be detected colorimetrically, since it has an absorbance of 440nm. At 2 hours after the reagent was added, the reading was done on a plate reader at 440 nm.

The results obtained are shown, as shown in Figure 4, as the percentage of cell death for each treatment referred to the death produced by the CPT. Death protection was observed by the mesylate of gemifloxacin reaching 34% at 10 μΜ. From these results it is concluded that gemifloxacin shows a protective effect of the death of human cells of neuronal origin caused by apoptosis.

 (ii) Protection of apoptosis determined by activity of active caspase 3/7.

 Active caspase 3/7, as a method of quantification of apoptosis, was analyzed using the Apo-ONE® Homogeneous Caspase-3/7 kit (Promega).

Caspase 3 and caspase 7 are cysteine proteases characterized by mediating the breakdown of other proteins, being effector caspases that trigger apoptotic signaling. Caspase 3/7 activation was quantified by treatment with CPT with a pre-treatment for 24 hours with gemifloxacin mesylate (GFX).

SK-N-MC cells, in pass not exceeding 1 5, were seeded on 96 well plates treated for adherent cells with a cell concentration of 4x10 ⁴ cells / well; 3 wells of the plate were seeded for each test condition.

 After 24 h after planting the cells, cell pre-treatments (with gemifloxacin mesylate at 4 or 10 μΜ) were carried out for 24 h with 100 μΙ of total volume. After 24 hours of pre-treatment, cell treatments were carried out for 6 hours with 100 μΙ of total volume for the following conditions:

 - Control: culture medium (medium)

 - CPT: medium with CPT 50 uM.

 - CPT plus Z-VAD-fmk (Alexis): medium with CPT 50 μΜ plus Z-VAD-fmk 50 μΜ, as a positive inhibition control.

 - CPT plus gemifloxacin mesylate: med io with CPT 50 μT plus gemifloxacin mesylate at 4 or 10 μΜ.

The measurement of active caspase 3/7 was performed following the manufacturer's instructions. The lysis buffer was added to the cultured cells, which smooths and permeates the cells, and the substrate Z-DEVD-R1 10 of the effector caspases 3 and 7. The active caspase 3 or 7 causes the breakdown of the peptides DEVD of the substrate and emits fluorescence at 499/521 nm (emission / excitation), which is determined by the Infinite M200 fluorometer (Tecan).

 The results obtained are shown in Figure 5, determined in relative fluorescence units (RFU) of active caspase 3/7 after each treatment. The protection was determined by measuring the reduction of active caspase 3/7 compared to the treatment with CPT, with 29% and 52% being 4 and 1 0 μΜ of gemifloxacin mesylate, respectively. These results indicate that gemifloxacin shows a protective effect of apoptosis in human cells of neuronal origin. Z-VAD-fmk, a specific caspase inhibitor, inhibited the activation of caspase 3/7 by 88%.

(iii) Protection of apoptosis by determining DNA fragmentation by flow cytometry

 One of the characteristics that apoptotic cells show is DNA fragmentation. Based on this process, it is possible to label the DNA with the intercalating propidium iodide and by means of flow cytometry the percentage of cells that are in the early stages of the cell cycle (phase G0 / G1, charge n), of which they are doubling (phase S, load between n and 2n), of those in the last phase and mitosis (phase G2 / M, load 2n). In this way the dead cells are also determined by apoptosis, since they will have a load less than n, due to the fragmentation of DNA that occurs during apoptosis.

In this way, the DNA fragmentation produced after the CPT treatment for 6 h was analyzed with a pre-treatment during 24 h of gemifloxacin mesylate (GFX). The cells, in pass not exceeding 15, were seeded on 6-well plates treated for adherent cells with a cell concentration of 7.5x1 or ⁵ cells / well; 2 wells of the plate were seeded for each test condition.

After 24 hours after planting the cells, cell pre-treatments (with gemifloxacin mesylate at 4 or 10 μΜ) were carried out for 24 hours with 2 ml of total volume for the following conditions. After 24 hours of Pretreatment proceeded to the cell treatments for 6 h with 2 ml of total volume for the following conditions:

 - Control: culture medium (medium)

 - CPT: medium with CPT 50 uM.

 - CPT plus Z-VAD-fmk: medium with CPT 50 μΜ plus Z-VAD-fmk 50 μΜ, as a positive inhibition control.

 - CPT plus gemifloxacin mesylate: med io with CPT 50 μT plus gemifloxacin mesylate at 4 or 10 μΜ.

 After the treatment time the cells were collected together with their culture medium and centrifuged at 300 xg for 5 min. The medium was removed, a PBS wash was performed and fixed for 2 minutes with 500 µΙ of 70% ethanol at -20 ° C. Once fixed, they were centrifuged at 400 xg for 5 min, washed with PBS and propidium iodide was added at 0.05 mg / ml, diluted in a cycle buffer (0.1% sodium citrate, 0.3% nonidet P-40 and 0.02 mg RNAse / ml) and incubated 1 hour at 37 ° C. They were analyzed by flow cytometry, comparing the fluorescence of propidium iodide against the amount of DNA. The percentage of apoptosis was measured on the sub-G1 region (fragmented DNA) of each of the conditions.

 The results obtained are shown in Figure 6, as the percentage of cells in apoptosis (with fragmented DNA) of each treatment referred to apoptosis produced by the CPT. A protection of 30% at 4 μΜ of gemifloxacin mesylate was observed. These results indicate that gemofloxacin shows a protective effect of apoptosis in human cells of neuronal origin. Z-VAD-fmk, a specific caspase inhibitor, inhibited the number of apoptotic cells by 90%.

EXAMPLE 5

 Effect of gemifloxacin on acetylcholinesterase (AChE) activity

Acetylcholinesterase (AChE) is the enzyme that degrades the neurotransmitter acetylcholine (ACh), forming choline and acetate and preventing ACh activity at the nervous synapse. The activity of this enzyme has been related to Alzheimer's disease (AD), since: (i) it is detected less ACh in the brains of patients with AD than in healthy controls, (ii) ACh is a fundamental neurotransmitter for the creation of memories, learning and other intellectual activities that are compromised in AD, and (iii) AChE degrades ACh, so AChE inhibition is a therapeutic target of AD.

 Inhibition of the AChE enzyme produced in vitro by gemifloxacin mesylate was analyzed. This measure is based on the method of Ellman (Ellman et al. Biochem Pharmacol 1961; 147 [393]: 406): Acetylcholine iodide is used as a synthetic substrate, which in the presence of the AChE enzyme of Electrophurus electritus is transformed into acetate and thiocol ina. Thiocholine reacts with DTN B (5,5'-dithiobis-2-nitrobenzoic acid or El lman reagent) producing a yellow compound, 4-nitrotiolate, with absorbance at 412 nm that is measured in the BechmarkPlus plate reader (Biorad). As the inhibition control compound BW284c51 is used, which is a specific AChE inhibitor.

 The results obtained are shown in Figure 7 as the percentage of AChE activity in vitro of each treatment referred to the control. An inhibition of the activity of the enzyme was observed with 4, 10 and 40 μΜ of gemifloxacin mesylate of 54%, 46% and 29%, respectively, while the specific inhibitor BW284c51 inhibited the activity of the enzyme by 85%.

Subsequently, the cell AChE assay was performed using the SK-N-MC neuronal cells, which have acetylcholinesterase activity so they are a good cellular model. The treatments were carried out on the cells and after 24 h they were lysed and the AChE activity measurement test based on the Ellman method was performed, in the same way as in vitro. In this case, the iso-OMPA (tetraisopropyl pyrophosphoramide) non-specific cholinesterase inhibitor was used for all treatments. The results obtained are shown in Figure 8, as the percentage of cellular AChE activity of each treatment referred to the control and normalized by the amount of total protein. Inhibition of enzyme activity was observed with 1 0, 40 and 1 00 μΜ of gemifloxacin mesylate of 21%, 36% and 22% respectively. The BW284c51 inhibitor inhibited the activity of the enzyme. These results together indicate that gemifloxacin is able to inhibit both the enzyme AChE in vitro and in vivo.

EXAMPLE 6

 Gemifloxacin blood brain barrier passage

(i) Analysis of the passage of blood brain barrier by passive diffusion analyzed by PAMPA test

 A trial was conducted that aimed to predict whether gemifloxacin is capable of crossing the blood-brain barrier (BHE) by passive diffusion. The barrier was mimicked in an in vitro system that allowed the evaluation of the compound without the use of cells. To do this, the so-called PAMPA (Parallel Artificial Membrane Permeation Assay) test was carried out, which uses a sandwich system which determines the passage of compounds by means of passive diffusion avoiding active transport. As a positive control, verapamil, a compound with high permeability to BHE, was used, while as a negative control, theophylline, a compound that does not cross BHE, was used.

 To mimic the BHE, a commercial lipid mixture derived from pig brain was used with a lipid phosphol composition very similar to that constituting the human barrier, and called PBL (Porcine Polar Brain Lipid). This compound was stored at -20 ° C dissolved in dodecane at 1 00 g / mL in glass vials. The gemifloxacin, verapamil and theophylline mesylate compounds were stored at -20 ° C and used at 100 μΜ in a phosphate buffer at pH 7.4 containing monobasic sodium phosphate (0.41 M) and dibasic potassium phosphate (0.287M) in 1% DMSO .

In a 96-well filter plate with a pore size of 45 μιτι (MAIPN4550) 5 μ ί of PBL was added at 20 pg / mL, and after two minutes, 300 μί of the phosphate buffer was added. This plate was considered the acceptor plate and was placed on the top of the sandwich. On another 96-well plate that was assembled with the previous one (MATRNP550), 300 μί of gemifloxacin, verapamil or theophylline mesylate was added, at 100 μ trip and in triplicate. In addition, a target that included only 1% of DMSO was included in the phosphate buffer used. This plate was called the donor plate. The acceptor plate was placed on the donor plate forming the sandwich system. The compounds under study spread from the wells of the donor plate to the corresponding wells of the acceptor plate during 18h in which the system remained intact. The remaining compound prepared was kept in the same conditions of humidity, temperature and darkness as the sandwich system constituted by the plates. After this time, 100 L of the wells of the donor and acceptor plates were transferred to a special 96-well plate for UV reading. In addition, 1 00} L of the compounds prepared for the performance of the test were transferred, while retaining the plates (basal wells). The UV plate was introduced into a spectrophotometer in which a UV scanner was carried out from 230 to 498 nm, with readings every 4 nm. From the spectrophotometric data, the percentage of barrier passage was calculated as well as the effective permeability (P _e ) as described in the literature (Wexler et al. J. Biomol Screen 2005; 10 [4]: 383-90). Next, the appropriate wavelength was selected in each case and the data referring to said wavelength were taken for the wells of the acceptor plate, donor or the basal wells. From these data, the percentage of BHE passage was calculated, estimating 1 00% with the absorbance of the average of the basal wells, so that the percentage of compound existing in the acceptor and donor wells could be calculated after the time of plate contact. To calculate the Pe, the following formula was applied:

Pe? C x ™ * ™ Ln 1 ~ J

 [Drug] balance

Where:

Q—

(V _D x V _A ) x Area x Time

[Acceptable drug] = Absorbance of acceptor well

[Drug] _eq u¡i¡br¡o = Aborbance of the average of the basal wells / 2 V _A = Volume of acceptor well = 0.3 cm ³

V _D = Volume of donor well = 0.3 cm ³

Area = 0.24 cm ²

 Time = 64,000 s

The results of the BHE step are shown in Figure 9, where the two parameters related to diffusion through the BHE are represented. Gemifloxacin has an efficient barrier passage of approximately 37% (P _e = 4.4 ± 0.4-10 ^"6 cm / s), and clearly superior to the negative control, theophylline, whose barrier passage is less than 5% (P _e = 0.4 ± 0.3-10 ^"6 cm / s).

(ii) Analysis of the blood-brain barrier passage in adult zebrafish by determination by UPLC / MS

The aim of the trial was to determine whether gemifloxacin (GFX) was able to cross the blood brain barrier (BHE), determining the bioavailability of the compound in the brain of an adult zebrafish.

 In this trial, zebra (Danio rerio) adults of both genera of the wild AB strain were used. The animals were kept in a constant light / dark cycle from 12/12 h at 26 ± 1 ° C in an automated commercial water recirculation tank system (Aquaneering, US). Water and environment conditions were maintained according to the manufacturer's instructions. All experimental procedures were carried out in accordance with the Directive of the Council of the European Community 86/609 / EEC, of November 24, 1986. The procedures were performed under the supervision of veterinary personnel and were approved by the ethical committee of NEURON BPh.

The adult zebrafish were treated by immersion of the compound without renewal frequency (static test) at a dose of 1,000 mg / kg following a kinetics of treatment times that ended with the humanitarian sacrifice and extraction of the brains of the animals to 15 min, 30 min, 1 h, 4 h and 24 h post-treatment. In the handling processes, strict precautions were taken to prevent contamination. Four animals were used for each experimental group, and the trial had a total of 24 zebrafish divided into the following administration guidelines:

 or 4 control animals, treated with system recirculation water and humanely slaughtered at the end of the test (24 hours post-treatment).

 or 20 animals treated with the compound gemifloxacin (4 animals per condition) diluted in recirculation water of the system at a dose of 1,000 mg / kg without replacement of the substance during the duration of the test.

 After the exposure time of the substances under study, the BHE passage of gemifloxacin in the brains of the fish was determined by the UPLC / MS technique, as shown in Figure 10. The equipment used for this purpose was an Acquity / Quatro Premier XE (Waters) with Quatro Premier XE (Waters) mass detector. The mobile phase consisted of methanol (solvent A) and 0.1% formic acid (solvent B). The elution gradient was: 0-4 min 90% A and 10% B. The column temperature was 35 ° C with a flow of 0.3 mL / min and a sample injection volume of 5 μί. The MS conditions set were: capillary voltage of 4 kV, cone voltage of 20 V in positive mode and a temperature of 1 20 ° C. The measurement range selected in SCAN mode was 160-1000 m / z.

 The results of the study demonstrate that gemifloxacin, surprisingly, crossed the BHE of adult zebrafish since its presence is observed in the animal's brain, presenting a maximum detection peak at 1 h post-treatment with gemifloxacin.

 Therefore, this trial concludes that gemifloxacin crosses the BHE of adult zebrafish, and accesses the brain.

Claims

one . Use of gemifloxacin, a pharmaceutically acceptable salt, prodrug and / or solvate thereof in the preparation of a pharmaceutical composition for the prevention and / or treatment of:  to. neurodegenerative diseases,  b. mild cognitive impairment,  C. cognitive deficits,  d. dementias  and. diseases associated with aging, and  F. pathological processes associated with age and progeria. 2. Use according to claim 1 wherein the prevention or treatment of:  to. neurodegenerative diseases,  b. mild cognitive impairment,  C. cognitive deficits,  d. dementias  and. diseases associated with aging, and  F. pathological processes associated with age and progeria  It takes place through neuroprotection. 3. Use according to claim 2 wherein the neuroprotection occurs  by direct inhibition of neuronal death 4. Use according to claim 3, wherein the neuronal death is caused by a neurotoxic substance. 5. Use according to any one of the preceding claims, wherein neurodegenerative disease is selected from Alzheimer's disease, mild cognitive impairment, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, disease of Creutzfeldt-Jakob, epilepsy, cognitive and / or psychomotor deficits, ataxias, dementias, cerebrovascular diseases and Alexander's disease. 6. Use according to any of the preceding claims, wherein the neurodegenerative disease is selected from Alzheimer's disease, mild cognitive impairment, Huntington's disease, Parkinson's disease, Creutzfeldt-Jakob disease, epilepsy, cognitive and / or psychomotor deficits, ataxias, dementias, cerebrovascular diseases and Alexander's disease. 7. Gemifloxacin, a pharmaceutically acceptable salt, prodrug and / or solvate thereof for use in the prevention and / or treatment of:  to. neurodegenerative diseases,  b. mild cognitive impairment,  C. cognitive deficits,  d. dementias  and. diseases associated with aging, and  F. pathological processes associated with age and progeria. 8. Gemifloxacin according to claim 7 wherein the prevention and / or treatment of:  to. neurodegenerative diseases,  b. mild cognitive impairment,  C. cognitive deficits,  d. dementias  and. diseases associated with aging, and  F. pathological processes associated with age and progeria,  It takes place through neuroprotection. 9. Gemifloxacin according to claim 8 wherein neuroprotection is produced by direct inhibition of neuronal death. Gemifloxacin according to claim 9 wherein the neuronal death caused by a neurotoxic substance. eleven . Gemifloxacin according to any of claims 7-10 wherein the neurodegenerative disease is selected from disease of Alzheimer's disease, mild cognitive impairment, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Creutzfeldt-Jakob disease, epilepsy, cognitive and / or psychomotor deficits, ataxias, dementias, cerebrovascular diseases and Alexander's disease. 12. Gemifloxacin according to any of claims 7-1 1, wherein the neurodegenerative disease is selected from Alzheimer's disease, mild cognitive impairment, Huntington's disease, Parkinson's disease, Creutzfeldt-Jakob disease, epilepsy, cognitive deficits and / or psychomotors, ataxias, dementias, cerebrovascular diseases and Alexander's disease. 13. Method for the prevention and / or treatment of:  to. neurodegenerative diseases,  b. mild cognitive impairment,  C. cognitive deficits,  d. dementias  and. diseases associated with aging, and  F. pathological processes associated with age and progeria.  which comprises administering to said subject a therapeutically efficient amount of gemifloxacin, or a pharmaceutically acceptable salt, prodrug and / or solvate thereof.