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1. WO1999000117 - PROCEDES ET REACTIFS NEUROPROTECTEURS

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We claim:

1. A method for limiting damage to neuronal cells by ischemic or epoxic conditions, comprising administering to an individual a ptc therapeutic in an amount effective for reducing cerebral infarct volume relative to the absence of administeration of the ptc therapeutic.
2. A method for protecting cerebral tissue of a mammal against the repercussions of ischemia which comprises administering to the mammal in need thereof a therapeutically effective amount of the ptc therapeutic.
3. A method for the treatment of cerebral infarctions which comprises administering to a patient in need thereof a therapeutically effective amount of the ptc therapeutic.
4. A method for the treatment of cerebral ischemia which comprises administering to a patient in need thereof a therapeutically effective amount of the t therapeutic.
5. A method for the treatment of stroke which comprises administering to a patient in need thereof a therapeutically effective amount of the ptc therapeutic.
6. A method for the treatment of transient ischemia attack which comprises administering to a patient in need thereof a therapeutically effective amount of the ptc therapeutic.
7. The method of any of claims 1 -6, wherein the ptc therapeutic binds to patched and mimics hedgehog-mediated patched signal transduction.
8. The method of claim 7, wherein the ptc therapeutic is a small organic molecule.
9. The method of claim 7, wherein the binding of the ptc therapeutic to patched results in upregulation of patched and/or gli expression.
10. The method of any of claims 1-6, wherein the ptc therapeutic is a small organic molecule which interacts with neuronal cells to mimic hedgehog-mediated patched signal transduction.
1 1. The method of any of claims 1 -6, wherein the ptc therapeutic mimics /ze_tge/.øg-mediated patched signal transduction by altering the localization, protein-protein binding and/or enzymatic activity of an intracellular protein involved in a patched signal pathway.
12. The method of any of claims 1-6, wherein the ptc therapeutic alters the level of expression of a hedgehog protein, a patched protein or a protein involved in the intracellular signal transduction pathway of patched.
13. The method of claim 12, wherein the ptc therapeutic is an antisense construct which inhibits the expression of a protein which is involved in the signal transduction pathway of patched and the expression of which antagonizes /7e-/ge.røg-mediated signals.

14. The method of claim 13, wherein the antisense construct is an oligonucleotide of about 20- 30 nucleotides in length and having a GC content of at least 50 percent.
15. The method of claim 14, wherein the antisense oligonucleotide is selected from the group consisting of: 5'-GTCCTGGCGCCGCCGCCGCCGTCGCC;
5'-TTCCGATGACCGGCCTTTCGCGGTGA; and
5 ' -GTGCACGGAAAGGTGC AGGCC AC ACT

16. The method of claims 12, wherein the ptc therapeutic is a small organic molecule which binds to patched and regulates patc .c.i.-dependent gene expression.
17. The method of claim 1 1, wherein the ptc therapeutic is an inhibitor of protein kinase A. 18. The method of claim 17, wherein the PKA inhibitor is a 5-isoquinolinesulfonamide

19. The method of claim 18, wherein the PKA inhibitor is represented in the general formula:



wherein,
R] and R2 each can independently represent hydrogen, and as valence and stability permit a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl (such as a carboxyl, an ester, a formate, or a ketone), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, -(CH2)m-R8, -(CH2)m-OH, -(CH2)m-0-lower alkyl, -(CH2)m-0-lower alkenyl, -(CH2)n-0-(CH2)m-R8, -(CH2)m-SH, -(CH2)m-S-lower alkyl, -(CH2)m-S-lower alkenyl, -(CH2)n-S-(CH2)m-R8, or
R] and R taken together with N form a heterocycle (substituted or unsubstituted);
R3 is absent or represents one or more substitutions to the isoquinoline ring such as a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl (such as a carboxyl, an ester, a formate, or a ketone), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, -(CH2)m- Rg, -(CH2)m-OH, -(CH2)m-0-lower alkyl, -(CH2)m-0-lower alkenyl, -(CH2)n-0-(CH2)m-R8, -(CH2)m-SH, -(CH2)m-S-lower alkyl, -(CH2)m-S-lower alkenyl, -(CH2)n-S-(CH2)m-R8;
R8 represents a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; and
n and m are independently for each occurrence zero or an integer in the range of 1 to 6.

20. The method of claim 17, wherein the PKA inhibitor is cyclic AMP analog.
21. The method of claim 17, wherein the PKA inhibitor is selected from the group consisting of N-[2-((p-bromocinnamy l)amino)ethyl]-5-isoquinolinesulfonamide, 1 -(5-isoquinoline- sulfonyl)-2-methylpiperazine, KT5720, 8-bromo-cAMP, dibutyryl-cAMP and PKA Heat Stable Inhibitor isoform α.

22. The method of claim 5, wherein the stroke is a thrombotic stroke.
23. The method of claim 5, wherein the stroke is an embolic stroke
24. The method of claim 1 , wherein the hypoxic conditions result in cerebral hypoxia.
25. The method of claim 1 , wherein the conditions result in progressive loss of neurons due to oxygen deprivation
26. The method of any of claims 1-6, wherein patient is being treated prophylactically.
27. The method of claim 1, wherein the patient is hypotensive.
28. The method of claim 1 , wherein the conditions result in progressive loss of neurons due to oxygen deprivation
29. The method of any of claims 1-6, wherein the ptc therapeutic is administered as part of a therapy including administering one or more of an anticoagulation, an antiplatelet agent, a thrombin inhibitors, and/or a thrombolytic agent.
30. The method of any of claims 1-6, wherein the ptc therapeutic is administered as part of a therapy including vascular surgery.
31. The method of claim 30, wherein the vascular surgery comprises carotid endarterectomy.

32. The method of any of claims 1-6, wherein treatment of the patient with the ptc therapeutic results in atleast a 25% reduction in cerebral infarct volumes relative to absence of treatment with the ptc therapeutic.
33. The method of claim 32, wherein treatment of the patient with the ptc therapeutic results in atleast a 50% reduction in cerebral infarct volumes relative to absence of treatment with the ptc therapeutic.

34. The method of claim 32, wherein treatment of the patient with the ptc therapeutic results in atleast a 70% reduction in cerebral infarct volumes relative to absence of treatment with the ptc therapeutic.
35. A therapeutic preparation of a small molecule antagonist oϊ patched, which patched antagonist is provided in a pharmaceutically acceptable carrier and in an amount sufficient to provide protection against neuronal cell death under ischemic and/or hypoxic conditions.
36. The preparation of claim 35, which patched antagonist binds to patched.
37. The preparation of claim 35 , wherein the patched antagonist is provided in an amount sufficient to produce, upon a dosage regimen of 7 days, at least a 70% decrease in infarct volume in an MCAO model relative to the absence of the patched antagonist.
38. The preparation of claim 37, wherein the patched antagonist is provided in an amount sufficient to produce, upon a dosage regimen of 3 days, at least a 70% decrease in infarct volume in an MCAO model relative to the absence oϊ the patched antagonist.
39. A method for limiting damage to neuronal cells by ischemic or epoxic conditions, comprising aclministering to a patient a gene activation construct which recombines with a genomic hedgehog gene of the patient to provide a heterologous transcriptional regulatory sequence operatively linked to a coding sequence of the hedgehog gene.

SUBSTITUTE SHEET (RULE fcθ)