Parthenolide and its derivative for use in the treatment of axonal damage

Abstract

The present invention relates to a compound reducing microtubule detyrosination in axonal tips selected from the group consisting of tubulin carboxypeptidase inhibitors and tubulin tyrosine ligase activators and combinations thereof for use in the treatment of axonal damage.

1 . A compound reducing microtubule detyrosination in axonal tips selected from tubulin carboxypeptidase inhibitors selected from the group consisting of parthenolide or a racemate, enantiomer, stereoisomer, solvate, hydrate, pharmaceutically acceptable salt, ester, a derivative selected from 8-, 9- or 14-hydroxyparthenolide and dimethylamino parthenolide, and a structural analogue selected from cnicin or a racemate, enantiomer, stereoisomer, solvate, hydrate, pharmaceutically acceptable salt and/or ester for use in the treatment of axonal damage, wherein the axonal damage is an injury of the peripheral nervous system or a cranial nerve, or is associated with a denervation of an injured or transplanted cornea, and wherein the compound is for use in axonal regeneration. 
     
     
         2 . (canceled) 
     
     
         3 . The compound for use according to  claim 1 , wherein the axonal damage is an injury of the sciatic nerve or the optic nerve. 
     
     
         4 . The compound for use according to  claim 1 , wherein the axonal damage is associated with peripheral neuropathy or glaucoma. 
     
     
         5 . The compound for use according to  claim 1 , wherein the axonal damage is associated with axotomized fibers in the lesioned optic nerve or trigeminal nerve, particular its ophthalmic branch. 
     
     
         6 . A pharmaceutical composition comprising as an active ingredient a compound reducing microtubule detyrosination in axonal tips selected from tubulin carboxypeptidase inhibitors selected from the group consisting of parthenolide or a racemate, enantiomer, stereoisomer, solvate, hydrate, pharmaceutically acceptable salt, ester, a derivative selected from 8-, 9- or 14-hydroxyparthenolide and dimethylamino parthenolide, and a structural analogue selected from cnicin or a racemate, enantiomer, stereoisomer, solvate, hydrate, pharmaceutically acceptable salt and/or ester thereof for use in the treatment of axonal damage. 
     
     
         7 . (canceled) 
     
     
         8 . The pharmaceutical composition for use according to  claim 5 , wherein the composition is formulated for local such as intraneural or periradicular application, or for systemic application such as intraperitoneal, intravenous, subcutaneous or oral application. 
     
     
         9 . The pharmaceutical composition for use according to  claim 5 , wherein the composition is formulated for intraocular application, particularly as eye drops. 
     
     
         10 . Use of a compound reducing microtubule detyrosination in axonal tips selected from tubulin carboxypeptidase inhibitors selected from the group consisting of parthenolide or a racemate, enantiomer, stereoisomer, solvate, hydrate, pharmaceutically acceptable salt, ester, a derivative selected from 8-, 9- or 14-hydroxyparthenolide and dimethylamino parthenolide, and a structural analogue selected from cnicin or a racemate, enantiomer, stereoisomer, solvate, hydrate, pharmaceutically acceptable salt and/or ester thereof for the manufacture of a medicament for the treatment of axonal damage, wherein the axonal damage is an injury of the peripheral nervous system or a cranial nerve, or is associated with a denervation of an injured or transplanted cornea and wherein the compound is for use in axonal regeneration. 
     
     
         11 . (canceled) 
     
     
         12 . The use according to  claim 8 , wherein the axonal damage is an injury of the sciatic nerve or the optic nerve, or is associated with axotomized fibers in the lesioned optic nerve or trigeminal nerve, particular its ophthalmic branch. 
     
     
         13 . A method of regenerating axonal damage, wherein the axonal damage is an injury of the peripheral nervous system or a cranial nerve, or is associated with a denervation of an injured or transplanted cornea, the method comprising administering to a subject a therapeutically effective amount of a compound reducing microtubule detyrosination in axonal tips selected from tubulin carboxypeptidase inhibitors of parthenolide or a racemate, enantiomer, stereoisomer, solvate, hydrate, pharmaceutically acceptable salt, ester, a derivative selected from 8-, 9- or 14-hydroxyparthenolide and dimethylamino parthenolide, and a structural analogue selected from cnicin or a racemate, enantiomer, stereoisomer, solvate, hydrate, pharmaceutically acceptable salt and/or ester thereof. 
     
     
         14 . (canceled) 
     
     
         15 . The method according to  claim 10 , wherein the axonal damage is an injury of the sciatic nerve or the optic nerve, or is associated with axotomized fibres in the lesioned optic nerve or trigeminal nerve, particular its ophthalmic branch.