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US20040185429A1 - Method for discovering neurogenic agents - Google Patents

Method for discovering neurogenic agents Download PDF

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US20040185429A1
US20040185429A1 US10/728,652 US72865203A US2004185429A1 US 20040185429 A1 US20040185429 A1 US 20040185429A1 US 72865203 A US72865203 A US 72865203A US 2004185429 A1 US2004185429 A1 US 2004185429A1
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neurogenesis
neurons
neural progenitor
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cells
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Judith Kelleher-Andersson
Karl Johe
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Priority to US13/658,623 priority patent/US20130045487A1/en
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    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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Definitions

  • Hippocampus is the well-known center of learning, memory, and other cognitive functions, processes which new information are added, edited, stored, and recalled constantly throughout life. Since hippocampus is also the most potent neurogenic area of the brain, many studies have been undertaken to establish whether neurogenesis may be the cellular mechanism to structurally accommodate the ever-increasing volume of cognitive processing to be handled. Thus, it has been shown that at least some of the newly born neurons, marked by genetic markers, do mature to be electrophysiologically active and integrate into the existing neuronal circuitry of the hippocampus. Ablation of the neurogenesis in rats leads to decreased cognitive capabilities in several behavior tests. Thus, the existing data demonstrate that neurogenesis significantly contributes to the normal hippocampal physiology.
  • neurogenesis becomes more wide-spread and perhaps functionally diverse.
  • the newly born neurons of the subependyma also referred to as subventricular zone
  • the newly born neurons have short survival period.
  • a compound that can stimulate the endogenous neurogenesis either in a disease state or in a healthy state may be an effective drug for a number of human nervous system diseases.
  • the current limitation is the lack of an effective, predictive in vitro assay that can be used to select a neurogenic compound for clinical drug development.
  • Disclosed here is a novel, in vitro assay, which is effective and predictive, to be useful for discovering a compound that promotes neurogenesis in vivo.
  • classes of compound structures that are shown to be particularly effective in promoting the neurogenesis.
  • This invention relates to the method of discovering a neurogenic drug to treat neurologic, psychiatric, and aging-related disorders. It also relates to the use of Fused Imidazoles, Aminopyrimidines, Nicotinamides, Aminomethyl Phenoxypiperidines and Aryloxypiperidines for use as therapeutic agents and analytical reagents by means of promoting neurogenesis. More particularly this invention relates to these agents as therapeutics for prevention and treatment of neurological diseases in mammals and reagents for detecting neurogenesis and proliferation.
  • antidepressants are thought to work by increasing the levels of monoamines available for post-synaptic receptors.
  • classes of agents working apparently by the “monoaminergic hypothesis of depression” include the selective serotonin uptake inhibitors (SSRIs) like fluoxetine, the mixed noradrenaline/serotonin transporter blockers like tricyclic agent imipramine and noradrenaline uptake inhibitors like desipramine.
  • SSRIs selective serotonin uptake inhibitors
  • fluoxetine the mixed noradrenaline/serotonin transporter blockers like tricyclic agent imipramine
  • noradrenaline uptake inhibitors like desipramine.
  • the antidepressant-induced increase in intraneuronal biogenic amines occurs quite rapidly.
  • the antidepressant-induced improvement in clinical behavior requires weeks of daily administration.
  • the neurogenic theory of depression though not conclusive, has strong supportive data including the finding that neurogenesis is actually requisite for antidepressant behavioral improvement in the novelty suppressed feeding model (Santarelli et al., 2003).
  • a therapeutic benefit from hippocampal neurogenesis is further supported by the finding of hippocampal atrophy in depression, where MRI imaging studies identified a reduction in the right and the left hippocampal volumes in individuals with major depression (Sheline et al., 1996; Bremner et al., 2000; Mervaala et al., 2000).
  • Neurogenesis can be characterized as three successive stages: proliferation of endogenous stem cells and precursors, differentiation into neurons and neuron maturation with formation of viable synaptic connections (plasticity).
  • the hippocampal volume loss in depression could potentially be caused by 1) inhibition of the endogenous hippocampal stem cell proliferation in the dentate gyrus, 2) inhibition of differentiation and dendrite development and 3) by loss of neurons (apoptosis) and their dendritic structure.
  • apoptosis is observed in depression, hippocampal apoptosis as measured by DNA fragmentation from depressed patients appears to play only a minor role in the volume loss (Lucassen et al., 2001).
  • CREB phosphorylation is increased in animals administered rolipram chronically (Nakagawa et al., 2002) and antidepressants that either increase Ca2+/CaM-kinases or cAMP could cause the phosphorylation of CREB in the nucleus (reviewed by D'sa and Duman 2002). They further suggest that the phosphorylated CREB then binds to CRE binding site to promote the expression of BDNF and bcl-2, that appear critical to cell survival and plasticity.
  • neurogenesis is critical for antidepressant activity is it also sufficient and is the mechanism by which the neurogenesis occurs or timing of neurogenesis also critical to the therapeutic activity?
  • Rolipram an antidepressant that works by increasing cAMP levels and is neurogenic in animals (Nakagawa et al., 2002) was effective in our primary in vitro neurogenesis screen. This suggests that our primary in vitro screen would include those agents that might promote neurogenesis by targeting the cAMP/pCREB/BDNF pathway. This does not necessarily exclude all other neurogenesis mechanisms for our NSI compounds. If the target of these neurogenic agents are important for behavioral activity where three separate chemically diverse classes showed in vitro assay efficacy differences and that the mechanism for all does not overlap at the point of CREB phosphorylation and BDNF expression then we might expect very different effects on behavioral activities in depression models.
  • AD therapeutics that regulate neuronal function and survival
  • AIT-082 promotes memory enhancement in AD individuals potentially by stimulating endogenous trophic factors (Ritzman and Glasky, 1999; Rathbone et al., 1999). So the use of agents to promote increased survival and function of the remaining available neurons appears to have some therapeutic value.
  • Hippocampus is one of the main brain regions where neurogenesis in adult brain has been documented across several vertebrate species, including monkeys and humans (e.g., Gould et al., 2001; Eriksson et al., 1998). In fact, adult hippocampal neurogenesis contributes functionally to cognitive capacity. Shors et al. (2001) reported that inhibition of neurogenesis in adult rat hippocampus, in the absence of the destruction of existing neurons, caused impaired memory function. Many studies observed that degenerative conditions induced neurogenesis in mature mammalian brains, suggesting the existence of a natural repair pathway by means of neurogenesis.
  • a number of other inducers of neurogenesis have been identified, including anti-depressants (Malberg et al., 2000; Czeh et al., 2001), and nitric oxide donors (Zhang et al., 2001) suggesting the usefulness of neurogenic agents for other diseases presenting cognitive-deficits, such as stroke and depression.
  • a small molecule that induces hippocampal neurogenesis that is blood brain barrier penetrable would allow for a potentially novel oral therapeutic for Alzheimer's disease.
  • AD therapeutics progressing in clinical trials, target neurodegeneration in the hopes of reducing the neuronal loss and cognitive decline.
  • Apoptotic death involving caspase pathways and DNA fragmentation has been measured in in vitro and animal models of AD and in Alzheimer's diseased brain tissue.
  • the extent of apoptosis leading to neuronal loss is of continual debate with most agreeing it has some effect, but that other neuronal death pathways definitely play a role (see Behl, 2000; Broe et al., 2001; Roth, 2001).
  • Concern that measures of upstream caspase markers in neurons from AD tissue may not proceed to degeneration has been suggested (Raina et al, 2001).
  • VEGF Vascular endothelial growth factor
  • a neurogenic drug is an agent that enhances the process of generating new neurons (neurogenesis).
  • neurogenesis occurs in the adult human brains under normal as well as under degenerative conditions and that such adult-generated neurons do contribute functionally to the brain physiology such as learning and memory.
  • These observations highlight the likelihood that a cellular mechanism for neurogenesis within adult human CNS, especially in hippocampus, does exist both as a normal physiological pathway and as a self-repairing pathway. What is lacking and contributes to permanent damage may be (1) the volume/persistence of neurogenesis and/or (2) the survival/maturation of the new neurons.
  • the objective of the neurogenesis screen as described here is to discover a compound that will significantly boost either of these processes.
  • Many neurological diseases including Alzheimer's disease, mild cognitive impairment, dementia, age-related cognitive decline, stroke, traumatic brain injury, spinal cord injury and the like are neurodegenerative conditions.
  • Neuropsychiatric diseases including depression, anxiety, schizophrenia and the like also show nerve cell dysfunction leading to cognitive, behavioral, and mood disorders.
  • a neurogenic drug would be beneficial for countering and treating these diseases.
  • the present invention discloses a method of discovering such a neurogenic drug.
  • Such drug will serve to prevent or treat neurodegenerative and neuropsychiatric disorders by promoting the birth of new neuron endogenously within the nervous system by administering the compounds of the present invention into the patient. This may involve delivery of the agents alone or together with transplanted stem cells or progenitor cells.
  • FIG. 1 Schematic description of neurogenesis processes captured in the assay and different potential sites of a neurogenic drug action.
  • FIG. 2 Detection of changes in cell number by Alamar Blue dye.
  • Alamar Blue a fluorescent dye, is used as an indicator of metabolic respiration to determine optimum plating density. Results at an initial plating density of 30,000 cells/well suggest a large difference in cell number on removal of mitogen from the N2b media (differentiation) versus N2b with mitogen (proliferation) conditions. This figure only describes total cellular activity, further markers are required to determine what cell types (e.g. neuronal, glial) are observed under differentiating media.
  • FIG. 3A Influence of known growth factors on proliferation and neurogenesis relative to control. Hippocampal progenitor cells were treated for seven days with differentiation media (without mitogen) in the presence or absence of 20 ng/ml of growth factor dosed every other day. Plates were treated with Alamar Blue as described in Methods, then fixed and stained with antibody (TuJ1) against type III beta-tubulin (neuronal marker). The 96-well plate was read in a fluorescent plate reader. Bars represent the Mean+SD from 4 wells per treatment.
  • FIG. 3B LIF effects on hippocampal cell proliferation and neurogenesis by manual cell counting. Hippocampal progenitor cells were treated for seven days with differentiation media (without mitogen) in the presence or absence of 20 ng/ml LIF. Three fields were analyzed per well for total number of cells (DAPI positive nuclei) and for total number of neurons (TUJI positive cells). Bars represent the Mean+SD from 4 wells per treatment. The percentage of neurons calculated for each treatment are as follows: 48.5+6.3% for controls and 53.6+1.15 for LIF. The non-TUJ1 positive cells are mainly astrocytic (GFAP+).
  • GFAP+ astrocytic
  • FIG. 4 Examples of proliferation profile of compounds selected from primary screening. Proliferation was measured after compound treatment for 7 days by Alamar Blue staining of live cells per well. Shown are relative values over the vehicle control.
  • FIG. 5 Example of neurogenesis profile of compounds selected from primary screening. After 7 days of compound treatment, the ratio of neuron number (TuJ1 stained) to the total nuclei number (Hoechst stained) was determined. Shown are the relative ratio of neuron:total cells for each compound over the vehicle control in percentage. Typical ratio for vehicle control is 40-50% neurons. The ratio can change by either increased differentiation of the cells to neurons, decreased proliferation of astrocytes, or increased proliferation of neuronal progenitors.
  • FIG. 6 Examples of neurogenesis profile of compounds selected from primary screening. After 7 days of compound treatment, the cells were stained with TuJ1 for neurons. The absolute number of TuJ1+ neurons per area was quantified and expressed as a relative value to the vehicle treated control.
  • a screening of a large number of unknown agents for discovering a candidate drug involves repeating the same test for several hundreds to several million times. This requires a great deal of reproducibility from the test.
  • a multipotent neural stem/progenitor cell line derived from human hippocampus was used. Cell lines derived from other CNS areas, including dentate gyrus of an adult brain, can also substitute.
  • a neural progenitor population derived as a stable cell line from partial differentiation of embryonic stem cells can also be used. For this purpose, a cell line is defined as a population of cells having been expanded for at least 10 cell-doublings.
  • Cell lines that are genetically engineered to enhance the cells' mitotic capacity can also be used.
  • the genetic modification consists of over-expression of functional c-myc protein intracellularly under a conditional activation system such as c-myc protein fused to a ligand-binding domain of an estrogen receptor.
  • Cell lines that are not genetically engineered are preferred and can also be used.
  • a progenitor population that upon differentiation generates both neurons and glia in a single culture has been used. Presence of glia, either astrocytes and/or oligodendrocytes or their precursors, are required to promote physiological maturation of nascent neurons born from their precursors in culture.
  • differentiation of the progenitors is initiated by withdrawing the mitogen from the culture. Serum as well as other growth-promoting factors should be avoided from the differentiating culture since they will significantly affect the reproducibility and interfere with the neurogenesis assay.
  • Neural stem/progenitor cells differentiate spontaneously in the absence of a mitogen. Undifferentiated mitotic cells are harvested by enzyme treatment to remove residual mitogen, in the preferred embodiment, basic fibroblast growth factor (bFGF). The collected cells are seeded into appropriate plates (standard 96-well or 384-well) pre-coated with the usual extra cellular matrix proteins (poly-D-lysine and fibronectin, for example) for attachment of the cells.
  • the initial seeding density can be within the range of about 2,000-125,000 cells per well of a 96-well plate.
  • the preferred density is 40,000 cells per well of a 96-well plate, which has been optimized for best signal-to-noise ratio.
  • Too low cell density retards the initiation of differentiation and results in poor plating efficiency, which interferes with the assay. Too high cell density leads to inhibition of neurogenesis due to cell-cell contact and paracrine factors, which also interferes with the assay.
  • the actual cell number can be proportionally decreased or increased depending upon the surface area of the culture substrate used. For example, for a 384-well plate, which has approximately 1 ⁇ 4 of the surface area of a 96-well plate, the initial seeding density should be decreased accordingly (1 ⁇ 4).
  • the key activity of a neurogenic drug is to increase the number of neurons generated from their precursors.
  • a molecule can bring about such increase in the neurogenesis by a number of different mechanisms. It can act as a mitogen for the neural stem/progenitor cells and increase the progenitor's cell number, which in turn results in increased number of neurons in the culture when differentiated. Or, it can act as a neuronal specification factor by promoting the stem/progenitor cell differentiation toward neurons in the expense of glia. This will also result in increased number of neurons in the culture, but without changing the overall cell number. Or, it can act as a mitogen for committed neuronal progenitors that differentiate only into neurons. Increasing this subpopulation would also increase the final number of neurons in the culture. Or, it can act as a survival factor to rescue immature neurons from undergoing cell death during differentiation, which will result in increased neurons (FIG. 1).
  • the assay method here captures all of these possibilities by allowing for sufficient time for these processes to unfold.
  • the assay is continued for seven days.
  • a minimum of three days from the onset of differentiation should be allowed for stable expression of definitive neuronal markers to appear.
  • a sufficient time is also required for a compound action on differentiation and/or proliferation to take place to a sufficient degree to be reliably detectable.
  • Manifestation of drug-induced changes in neuron number takes a minimum of three days for the human cells to be detectable.
  • the final neuron number is detected by immunostaining of the culture with antibodies against neurons and quantified by counting of the immunopositive neurons and/or by measuring the staining intensity.
  • the collected cells were seeded at 40,000 cells per well of 96-well plates pre-coated with extracellular matrix proteins (e.g., Biocoat PDL, Fisher).
  • the seeding media is a standard serum-free, growth factor-free, basal media that supports healthy neuronal/glial survival, such as N2 without phenol red.
  • the fluorescence level is proportional to the number of respiring cells in the culture and is a measure of a proliferative activity of a test agent (FIG. 2).
  • LIF leukemia inhibitory factor
  • an agent would be administered to treat a neurodegenerative disease.
  • the neurodegenerative disease would be Alzheimer's disease, dementia, mild cognitive impairment, aged-related cognitive decline, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, demyelination, stroke, spinal injuries, traumatic injuries, neuropathic pain, and the like.
  • this invention would be administered to treat a psychiatric disease.
  • the psychiatric disease is depression, post-traumatic stress syndrome, stress, anxiety, schizophrenia, sleep deprivation, cogntive dysfunction, amnesia, and the like.
  • an agent would be administered by any number of routes and multipotent stem cells or differentiated multipotent stem cells would be transplanted into brain.

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US8362262B2 (en) 2013-01-29
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US8674098B2 (en) 2014-03-18
EP1576134A4 (fr) 2007-05-30
US7858628B2 (en) 2010-12-28
WO2004053071A3 (fr) 2006-03-30
US20110135612A1 (en) 2011-06-09
US20110052552A1 (en) 2011-03-03
AU2003293409A1 (en) 2004-06-30
EP1576134A2 (fr) 2005-09-21
WO2004053071A9 (fr) 2012-08-16
US20130195816A1 (en) 2013-08-01
US8030492B2 (en) 2011-10-04
US20140147424A1 (en) 2014-05-29
US8846914B2 (en) 2014-09-30
US8058434B2 (en) 2011-11-15
US20120027733A1 (en) 2012-02-02
WO2004053071A2 (fr) 2004-06-24
US20100034784A1 (en) 2010-02-11
EP1576134B1 (fr) 2013-03-06

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