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WO2005016359A1 - Methode permettant de stimuler la remyelinisation - Google Patents

Methode permettant de stimuler la remyelinisation Download PDF

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Publication number
WO2005016359A1
WO2005016359A1 PCT/CA2004/001502 CA2004001502W WO2005016359A1 WO 2005016359 A1 WO2005016359 A1 WO 2005016359A1 CA 2004001502 W CA2004001502 W CA 2004001502W WO 2005016359 A1 WO2005016359 A1 WO 2005016359A1
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Prior art keywords
guanosine
remyelination
treated
cells
sections
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Inventor
Michel P. Rathbone
Eva S. Werstiuk
Shucui Jiang
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NEUROLOGICAL TECHNOLOGIES Inc
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NEUROLOGICAL TECHNOLOGIES Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • TITLE METHOD OF PROMOTING REMYELINATION FIELD OF THE INVENTION
  • the present invention relates to methods and compositions for promoting functional recovery and remyelination of the nervous system.
  • Traumatic spinal cord injury (SCI) induces a prominent local inflammatory reaction and persistent demyelination in the white matter around the lesion site. In humans this demyelination may persist for more than 50 years (1), which slows or disrupts impulse conduction, causing further functional loss. Unfortunately, extensive remyelination does not occur spontaneously.
  • the present invention provides a method of promoting the functional recovery of the nervous system comprising administering an effective amount of a purine nucleoside to an animal in need thereof.
  • the present invention further provides a method of promoting the remyelination of the nervous system comprising administering an effective amount of a purine nucleoside to an animal in need thereof.
  • the present invention also provides pharmaceutical compositions for enhancing the functional recovery and/or promoting remyelination of the nervous system comprising an effective amount of a purine nucleoside in admixture with a suitable diluent and/or carrier.
  • Figure 1(a)-(d) are graphs illustrating locomotor functional recovery (a and b), quantification of fast blue stained area at the lesion epicenter of spinal cords (c) and their relation after systemic treatment with guanosine (d).
  • Figure 2(a)-(d) are micrographs of cross-sections of spinal cords immunostained for myelin basic protein (MBP) (a and b) and Rip (c and d) from animals treated with guanosine (a and c) or vehicle controls (b and d). Guanosine treatment increased MBP-positive profiles (2a) and Rip-positive mature oligodendrocytes (2c) compared to vehicle-treated control animals (2b and 2d, respectively).
  • Figures 3(a) and (b) are micrographs of cross-sections of spinal cord segments.
  • the sections of spinal cords from guanosine-treated animals had NG2 immunopositive cells throughout the lesion site; but particularly in the dorsal columns of the white matter.
  • the NG2 immunopositive cells exhibited unipolar, bipolar and mutlipolar morphologies. Compared to cords from guanosine-treated animals, those from control animals (b) had far fewer NG2 immunopositive cells.
  • IC injury center
  • DC dorsal column
  • GM grey matter.
  • Scale bar 45 ⁇ M for both (a) and (b).
  • Figure 5 (left and right panels) are confocal fluorescent micrographs using antibodies against BrdU (green) and NG2 (red).
  • the left panel shows double staining for the vehicle-treated control cord and the right panel shows double staining for the guanosine-treated cord.
  • Figure 6(a) and (b) are mircographs of cross-sections of spinal cord segments immunostained for OX-42. Macrophages and microglia are OX-42 positive.
  • OX-42 positive cells were found throughout white matter around the lesion site in cords from both guanosine (a) and vehicle treated (b) animals. There was no difference in the number of OX-42-immnuoreactive cells between sections obtained from guanosine-treated and vehicle-treated control animals.
  • DETAILED DESCRIPTION OF THE INVENTION The present inventors have demonstrated that systemically administered guanosine enhances functional recovery and increases remyelination in the spinal cord of rats with established spinal cord injury.
  • the present invention provides a method of promoting the functional recovery of the nervous system comprising administering an effective amount of a purine nucleoside to an animal in need thereof.
  • the present invention also provides a use of an effective amount of a purine nucleoside to promote the functional recovery of the nervous system.
  • the invention further provides a use of an effective amount of a purine nucleoside in the manufacture of a medicament to promote the functional recovery of the nervous system.
  • the present invention further provides a method of promoting the remyelination of the nervous system comprising administering an effective amount of a purine nucleoside to an animal in need thereof.
  • the present invention further provides a use of an effective amount of a purine nucleoside to promote remyelination of the nervous system.
  • the present invention further provides a use of an effective amount of a purine nucleoside in the manufacture of the medicament to promote remyelination of the nervous system.
  • effective amount means an amount effective, at dosages and for periods of time necessary to achieve the desired result, e.g. promoting functional recovery and/or promoting remyelination.
  • animal as used herein includes all members of the animal kingdom, including humans. Preferably, the animal to be treated is a human.
  • the nervous system includes both the peripheral and central nervous systems.
  • the methods of the invention to promote the functional recovery and/or promote the remyelination in the nervous system can be used to treat any disease or condition of the central nervous system and/or peripheral nervous system wherein it is desirable to regain function and/or remyelination of the nervous system.
  • Such diseases or conditions include, but are not limited to, the demyelinating diseases such as multiple sclerosis and other neural diseases in which demyelination exerts a prominent source of dysfunction, including, but not limited to, neuromyelitis optica, acute disseminated encephalomyelitis, acute and subacute necrotizing hemorrhagic encephalitis and subacute necrotic myelopathy, stroke, trauma to the nervous system, anoxia induced through any means, damage induced by radiation, including therapeutic radiation, and demyelinating disorders of the peripheral nerves, including Bell's Palsy, compression injuries to nerves, and peripheral polyneuropathies such as acute and chronic demyelinating polyneuropathies and demyelination of nerves associated with any other disorder, including mononeuritis multiplex.
  • the demyelinating diseases such as multiple sclerosis and other neural diseases in which demyelination exerts a prominent source of dysfunction, including, but not limited to, neuromyelitis optica,
  • the present invention provides a method of treating a disease or condition wherein it is desirable to promote functional recovery or remyelination of the nervous system comprising administering an effective amount of a purine nucleoside to an animal in need thereof.
  • the present invention further provides a use of an effective amount of a purine nucleoside to treat a disease or condition wherein it is desirable to promote functional recovery of the remyelination of the nervous system.
  • the present invention also provides a use of an effective amount of a purine nucleoside in the manufacture of a medicament to treat a disease or condition wherein it is desirable to promote functional recovery of remyelination of the nervous system.
  • the method is used to treat a spinal cord injury.
  • treatment or treating means an approach for obtaining beneficial or desired results, including clinical results.
  • beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treating can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • the purine nucleosides used in the methods of the invention can be any purine nucleoside such as guanosine, inosine, adenosine and analogs thereof. Examples of analogs are provided below.
  • Suitable vehicles are described, for example, in Remington: The Science and Practice of Pharmacy (20 th Edition, ed. A.R. Green, Lippincott Williams & Wilkins, Baltimore, MD, USA, 2000).
  • the pharmaceutical compositions include, albeit not exclusively, the active compound or substance in association with one or more pharmaceutically acceptable vehicles or diluents, and contained in buffered solutions with a suitable pH and iso-osmotic with the physiological fluids.
  • the pharmaceutical compositions may additionally contain other agents such as other agents that can prevent the inhibition of apoptosis or that are used in treating inflammatory conditions or sepsis.
  • compositions can be for intralesional, intravenous, topical, rectal, parenteral, local, inhalant or subcutaneous, intradermal, intramuscular, intrathecal, transperitoneal, oral, and intracerebral use.
  • the composition can be in liquid, solid or semisolid form, for example pills, tablets, creams, gelatin capsules, capsules, suppositories, soft gelatin capsules, gels, membranes, tubelets, solutions or suspensions.
  • the pharmaceutical compositions of the invention can be intended for administration to humans or animals. Dosages to be administered depend on individual needs, on the desired effect and on the chosen route of administration.
  • the present invention also provides pharmaceutical compositions for enhancing the functional recovery and/or promoting remyelination of the nervous system comprising an effective amount of a purine nucleoside in admixture with a suitable diluent and/or carrier.
  • a suitable diluent and/or carrier comprising an effective amount of a purine nucleoside in admixture with a suitable diluent and/or carrier.
  • Example 1 Guanosine Enhances Remyelination MATERIALS AND METHODS All experiments were performed in compliance with the requirements of the Animals for Research Act of Ontario, Canada and the guidelines of the Canadian Council on Animal Care (CCAC), and had been approved by the Animal Research Ethics Board (AREB) of McMaster University. Surgical procedures. Adult female Wistar rats (280-300g weight, Charles River) were anaesthetised with isoflurane (3-5%): 0 2 (1L/min). Buprenorphine (0.03 mg/kg body weight, subcutaneously) was administered prior to surgery for pain relief. Spinal cords were surgically exposed and crushed with modified coverslip forceps (9-10) producing a moderate spinal cord injury (10).
  • rats were deeply anaesthetised and perfused transcardially with 4% paraformaldehyde (PFA) in phosphate buffered saline (PBS, pH 7.4). Segments of the spinal cords from T9 to L1 were removed and cryo-protected in 30% sucrose/PBS solution. A segment of each cord, extending from 5 mm rostral to 5 mm caudal to the lesion site was embedded in medium (Tissue- Tek® O.C.T. compound, Sakura Finetek U.S.A., Inc., Torrrance, CA).
  • MBP myelin basic protein
  • Rip was performed as described by other investigators (13,15). Briefly, sections were incubated with primary polyclonal antibodies to MBP (1:50; Chemicon Int., Temecula, CA) or monoclonal Rip antibodies (1 :200; Chemicon Int., Temecula, CA), at 4°C overnight. Following washing, sections were incubated with biotinylated goat anti-rabbit IgG (1 :400) for polyclonal MBP antibody or biotinylated horse anti-mouse IgG (1 :400) for monoclonal Rip antibody, respectively.
  • Guanosine treatment enhanced locomotor functional recovery. After a spinal cord crush of moderate severity motor function of the legs of rats recovered progressively, albeit incompletely, for 3 - 4 weeks, after which recovery plateaued, and no further improvement was observed (8). This plateau persisted in control rats that received vehicle injections from day 35 to day 42 after the crush ( Figure 1b). In contrast, rats treated daily with intraperitoneal injections of guanosine beginning 35 days after injury, showed a progressive improvement in locomotor performance over the next week, from a mean score on the locomotor scale of 10.8 to 11.7 (Figure 1b). The locomotor function of the guanosine-treated animals was statistically better than that of controls from the third day of treatment onwards (p ⁇ 0.05).
  • Guanosine treatment increased the number of Rip-positive cells.
  • T o determine whether the increased myelin in the cords of rats treated with guanosine was associated with mature oligodendrocytes, the inventors identified mature oligodendrocytes with a monoclonal antibody to Rip, a specific marker for nascent and mature oligodendrocytes (13,15,16). Rip intensely immunostained oligodendrocyte cell bodies and their processes ( Figure 2c and d).
  • Myelin is essential for normal nerve impulse conduction so that loss of the myelin sheath around axons may significantly contribute to the neurological deficits after SCI. Consequently, functional recovery may depend, at least in part, on remyelination (18).
  • These preliminary data indicate a possible causal relationship between remyelination induced by guanosine and the concomitant improvement in locomotor function.
  • the first unequivocal evidence of spontaneous myelin repair in the mammalian CNS was reported by Bunge et al. (17) and confirmed by others (18). However, remyelination is characteristically incomplete after injury to the CNS (18-19).
  • Oligodendrocyte precursors proliferate in the first two weeks after acute spinal cord injury in rats, but remain "silent" thereafter (14,20). However, those endogenous progenitors are able to differentiate into mature cells capable of myelinating axons (2-3). Attempts to promote myelin repair have, therefore, focused on stimulating or enhancing this natural process.
  • Successful manipulation of the glial response to injury, enabling stable restoration of structure and function, is a fundamental goal in the treatment of CNS damage.
  • the administration of neurotrophic factors provides one method of manipulating glial response.
  • oligodendrocyte progenitors 21 -22
  • dedifferentiate mature oligodendrocytes 23-24
  • myelination in vitro 25.
  • McTigue et al. (13) showed that in vivo administration of growth factors, neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF), via genetically engineered fibroblasts promoted oligodendrocyte proliferation and axonal sprouting.
  • BDNF brain-derived neurotrophic factor
  • guanosine stimulates several cell types to produce and release trophic factors, including bFGF, NGF and NT-3 in vitro as well as in vivo following traumatic injury (4), the effects of guanosine on remyelination and on recovery of function may be mediated by one or more of these growth factors.
  • the data show that systemic treatment with guanosine increased the number of mature Rip-positive oligodendrocytes in the region of the lesion, consistent with increased remyelination. This indicates that guanosine may induce remyelination by stimulating "silent" endogenous oligodendrocyte progenitors to proliferate and to differentiate into mature oligodendrocytes.
  • oligodendrocytes may result from stimulation of their migration from surrounding regions.
  • the inventors are investigating these possibilities. CONCLUSION These studies demonstrate a novel finding.
  • guanosine enhances function with concomitant increase in the number of mature oligodendrocytes and myelination.
  • the possibility exists that guanosine may have similar beneficial effects in higher animals and humans with stable, incomplete paraplegia resulting from spinal injuries.
  • NG2 is a cell surface antigen, chondronitin sulphate proteoglycan, and has been used to identify oligodendrocyte progenitor cells in adult mammalian CNS (review: Dawson et al., 2000).
  • NG2-positive (NG2+) cells can be detected after CNS injury and play a role in remyelination (Carroll et al., 1998; Keirstead et al., 1998; Levine and Reynolds, 1999; McTigue et al., 2001; review: Dawson et al., 2000).
  • NG2+ cells are likely oligodendroglial precursors (Levine and Stallcup, 1987; Keirstead et al. 1998; McTigue et al. 2001), but may include other cell types: macrophages, microglia and infiltrating Schwann cells (McTigue et al. 2001), precursors of astrocytes (Levine and Stallcup, 1987).
  • the inventors have found that cell proliferation (assessed by incorporation of bromodeoxyuridine, BrdU, into DNA) was higher in the cords of rats treated with guanosine (Fig. 3). In addition, the inventors have found that the number of NG2-reactive cells was also higher (Fig. 4) after guanosine treatment.
  • NG2+ cells were oligodendrocyte progenitor cells.
  • Cellular proliferation was examined by administering the thymidine analogue, bromodeoxyuridine (BrdU; 50 mg/kg, i.p. Sigma, B-5002), daily from day 35 to 41 after to the crush.
  • the rats were anaesthetized with sodium barbital (75-mg/kg-body weight), perfused transcardially with 4% paraformaldehyde and a segment, T9 to L1 , was removed from each spinal cord.
  • the tissues were processed histologically (McTigue et al., 2001).
  • PBS phosphate buffered saline
  • Figure 3 shows that the number of BrdU immunolabeled nuclei, and hence the number of mitotically active cells, was higher in cords of guanosine treated rats. This was particularly apparent in the dorsal colums at the epicenter of the crush site.
  • IC injury center
  • OX-42 expression Immunohistochemical techniques were similar to those described in Figure 3, except that the first antibody was a monoclonal OX-42 antibody (1 :200; CD11b, Research Diagnostics INC. Flanders NJ. OX-42). To determine whether guanosine treatment increased the number of macrophages and microglia, the number of OX-42 positive cells in guanosine treated and control sections was observed. Macrophages and microglia are OX-42 positive. OX-42 positive cells were found throughout white matter around the lesion site in cords from both guanosine (a) and vehicle treated (b) animals.
  • Rathbone MP Middlemiss PJ
  • Gysbers JW Andrew C, Herman MA, Reed JK et al. Prog Neurobiol 1999; 59:663-90.
  • Gysbers JW Guamieri MA, Mariggio T, Pietrangeo GF, Rathbone MP. Neurosci 2000; 96:817-824.
  • Keirstead HS Levine JM, Blackmore WF. Glia 1998, 22:161-170 21.
  • McMorris FA McKinnon RD. Brain Pathol 1996; 6:313-329.

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Abstract

L'invention concerne des méthodes et des compositions permettant de favoriser la récupération fonctionnelle et de stimuler la remyélinisation du système nerveux. Cette méthode consiste à administrer une dose efficace d'un nucléoside purinique à un animal nécessitant un tel traitement.
PCT/CA2004/001502 2003-08-19 2004-08-19 Methode permettant de stimuler la remyelinisation Ceased WO2005016359A1 (fr)

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US60/495,880 2003-08-19

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2302156A1 (fr) * 1997-09-02 1999-03-11 Children's Medical Center Corporation Procede pour moduler l'excroissance axonale des neurones du systeme nerveux central
WO2004022039A2 (fr) * 2002-09-03 2004-03-18 Neurological Technologies Inc. Nucleosides de purine utilises en tant qu'agents anti-apoptotiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2302156A1 (fr) * 1997-09-02 1999-03-11 Children's Medical Center Corporation Procede pour moduler l'excroissance axonale des neurones du systeme nerveux central
WO2004022039A2 (fr) * 2002-09-03 2004-03-18 Neurological Technologies Inc. Nucleosides de purine utilises en tant qu'agents anti-apoptotiques

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
JIANG ET AL.: "Guanosine promotes myelination and functional recovery in chronic spinal cord injury", NEROREPORT, vol. 14, 2003, LIPPINCOTT WILLIAMS & WILKINS, pages 2463 - 2467 *
MCADOO ET AL.: "Adenosine release upon spinal cord injury", BRAIN RESEARCH, vol. 854, 2000, ELSEVIER, pages 152 - 157 *
PHILLIS & GOSHGARIAN: "Adenosine and neurotrauma: therapeutic perspectives", NEUROLOGICAL RESEARCH, vol. 23, 2001, FOREFRONT PUBLISHING GROUP, pages 183 - 189 *

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