Neuroprotection in a rat model of multiple system atrophy

Research project P 14633 Neuroprotection in a rat model of multiple system atrophy Gregor K. WENNING 09.10.2000 After Parkinson`s disease (PD), multiple system atrophy (MSA) is the most common degenerative condition causing parkinsonism. On neuropathological examination of the brain of patients with parkinsonian presentation of MSA (MSA-P) there is cell loss and gliosis predominant in substantia nigra and striaturn, particularly the putamen (striatonigral degeneration). In MSA-P there is more rapid progression of motor disabilities than in PD, autonomic failure is seen in almost all cases, and mild non-disabling cerebellar and/or pyramidal signs are present in about half of these patients at some stage of their illness. To date the results of pharmacotherapy or neurosurgical intervention in MSA-P have been very disappointing. The present proposal will address the neuroprotective potential of agents that interact with putative mechanisms of neuronal cell death in MSA-P including excitotoxicity (remacemide, non-competitive NMDA receptor antagonist; riluzole, glutamate release blocker), energy impairment (coenzyme Q 10, mitochondrial respiratory chain enhancer), inflammation (aspirin, indomethacin, non-steroidal anti-inflammatory drugs), apoptosis (zVAD-fmk, caspase 1 and Ac-DFVD-cmk caspase 3 inhibitor). It is assumed that the proposed experimental studies will lead to effective neuroprotective treatment strategies in,patients with , MSA-P within the next 4-5 years. Agents have been chosen according to their neuroprotective, effects in experimental studies using animal models of neurodegenerative disorders such.as PD, HD or Alzheimer`s disease and according to their tolerability and feasibility in clinical phase I and II trials. The MSA-P rat model used in the proposed experiments was established by-the applicant in 1996. It is based on a combined unilateral sequential stereotaxic injection of a striatal (quinolinic acid) followed 3 days later by a nigral (6-hydroxydopamine) neurotoxin resulting in loss of both striatal and nigral projection neurons. The candidate agents will be injected intraperitoneally (remacernide, riluzole, coenzyme Q 10, aspirin, hidomethacin) or intracerebroventricularly (caspase I and 3 inhibitor) 30 minutes prior and 0, 12 and 24 hours after injection of the toxins, respectively. 14 days following the final administration animals will be processed for irrummohistochernistry using an anti- tyrosinehydroxylase antibody for nigral doparninergic neurons, an anti-DARPP-32 antibody for striatal projection neurons, an anti-glial fibrillary acidic antibody as markers for astroglia. Cell counts, lesion volume as well as optical density will be analysed on pre-defined levels and compared using t-tests and ANOVA.