Failure of caspase inhibition in the double-lesion rat model of striatonigral degeneration (multiple system atrophy).

Publisher: Springer Verlag Country of Publication: Germany NLM ID: 0412041 Publication Model: Print-Electronic Cited Medium: Print ISSN: 0001-6322 (Print) Linking ISSN: 00016322 NLM ISO Abbreviation: Acta Neuropathol Subsets: MEDLINE

Original Publication: Berlin : Springer Verlag

Caspase Inhibitors*; Amino Acid Chloromethyl Ketones/*therapeutic use ; Multiple System Atrophy/*drug therapy ; Neuroprotective Agents/*therapeutic use ; Oligopeptides/*therapeutic use; Amino Acid Chloromethyl Ketones/pharmacology ; Analysis of Variance ; Animals ; Basal Ganglia/drug effects ; Basal Ganglia/metabolism ; Basal Ganglia/pathology ; Behavior, Animal/drug effects ; Cell Count ; Cell Size/drug effects ; Disease Models, Animal ; Dopamine and cAMP-Regulated Phosphoprotein 32 ; Functional Laterality ; Immunohistochemistry/methods ; Male ; Motor Activity/drug effects ; Multiple System Atrophy/chemically induced ; Multiple System Atrophy/metabolism ; Nerve Tissue Proteins/metabolism ; Neurons/metabolism ; Neuroprotective Agents/pharmacology ; Oligopeptides/pharmacology ; Oxidopamine ; Phosphoproteins/metabolism ; Quinolinic Acid ; Rats ; Rats, Wistar ; Tyrosine 3-Monooxygenase/metabolism

In the present study we assessed the neuroprotective effects of the pan-caspase inhibitor z-VAD.fmk [N-benzyloxycarbony-valine-alanine-aspartate-(OMe)-fluoromethylketone], and the caspase-3 inhibitor Ac-DEVD.CHO (acetyl-aspartate-chloromethylketone) in the double-lesion rat model of striatonigral degeneration (SND), the core pathology underlying levodopa-unresponsive parkinsonism associated with multiple system atrophy (MSA). Male Wistar rats were divided into three groups, receiving either Ac-DEVD.CHO, z-VAD.fmk or normal saline before lesion surgery, comprising a sequential unilateral quinolinic acid (QA) lesion of the striatum followed by a 6-hydroxydopamine (6-OHDA) lesion of the ipsilateral medial forebrain bundle. At 2 weeks post lesion, all rats underwent testing of spontaneous nocturnal locomotor behavior in an automated Photobeam Activity System (FlexField). Immunohistochemistry was performed with tyrosine hydroxylase, dopamine and cyclic adenosine 3',5'-monophosphate-regulated phosphoprotein and glial fibrillary acidic protein antibodies. Morphometry was performed using computerized image analysis. Behavioral and morphological analysis failed to show striatal or nigral protection in caspase inhibitor-treated animals. Our findings suggest that anti-apoptotic strategies are unrewarding in the SND rat model and, therefore, alternative neuroprotective interventions such as anti-glutamatergic agents or inhibitors of microglial activation should be explored instead.

0 (Amino Acid Chloromethyl Ketones)
0 (Caspase Inhibitors)
0 (Dopamine and cAMP-Regulated Phosphoprotein 32)
0 (Nerve Tissue Proteins)
0 (Neuroprotective Agents)
0 (Oligopeptides)
0 (Phosphoproteins)
0 (acetyl-aspartyl-glutamyl-valyl-aspartal)
0 (benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone)
8HW4YBZ748 (Oxidopamine)
EC 1.14.16.2 (Tyrosine 3-Monooxygenase)
F6F0HK1URN (Quinolinic Acid)

Date Created: 20041119 Date Completed: 20050921 Latest Revision: 20131121

20250114

10.1007/s00401-004-0931-2

15549330