title: Failure of caspase inhibition in the double-lesion rat model of striatonigral degeneration (multiple system atrophy).
abstract: 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.
authors.affiliation: Clinical Department of Neurology, Innsbruck Medical University, Anichstrasse 35, 6020, Innsbruck, Austria.
authors.forename: Laura
authors.initials: L
authors.lastname: Mantoan
authors.forename: Nadia
authors.initials: N
authors.lastname: Stefanova
authors.forename: Karl E
authors.initials: KE
authors.lastname: Egger
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Jellinger
authors.forename: Werner
authors.initials: W
authors.lastname: Poewe
authors.forename: Gregor K
authors.initials: GK
authors.lastname: Wenning
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal / Q000187:drug effects; D061945:Caspase Inhibitors; D002452:Cell Count; D048429:Cell Size / Q000187:drug effects; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D007839:Functional Laterality; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D019578:Multiple System Atrophy / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D016627:Oxidopamine; D010750:Phosphoproteins / Q000378:metabolism; D017378:Quinolinic Acid; D051381:Rats; D017208:Rats, Wistar; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009842:Oligopeptides; D010750:Phosphoproteins; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D017378:Quinolinic Acid