Degeneration of Purkinje cells in parasagittal zones of the cerebellar vermis after treatment with ibogaine or harmaline.
The indole alkaloids ibogaine and harmaline are beta-carboline derivatives that cause both hallucinations and tremor. Reports that ibogaine may have potent anti-addictive properties have led to initiatives that it be tested for the treatment of opiate and cocaine addiction. In this study, ibogaine-treated rats were analysed for evidence of neurotoxic effects because human clinical trials of ibogaine have been proposed. We recently found that ibogaine induces a marked glial reaction in the cerebellum with activated astrocytes and microglia aligned in parasagittal stripes within the vermis. Based on those findings, the present study was conducted to investigate whether ibogaine may cause neuronal injury or degeneration. The results demonstrate that, after treatment with ibogaine or harmaline, a subset of Purkinje cells in the vermis degenerates. We observed a loss of the neuronal proteins microtubule-associated protein 2 and calbindin co-extensive with loss of Nissl-stained Purkinje cell bodies. Argyrophilic staining of Purkinje cell bodies, dendrites and axons was obtained with the Gallyas reduced silver method for degenerating neurons. Degenerating neurons were confined to narrow parasagittal stripes within the vermis. We conclude that both ibogaine and harmaline have selective neurotoxic effects which lead to degeneration of Purkinje cells in the cerebellar vermis. The longitudinal stripes of neuronal damage may be related to the parasagittal organization of the olivocerebellar climbing fiber projection. Since these drugs produce sustained activation of inferior olivary neurons, we hypothesize that release of an excitatory amino acid from climbing fiber synaptic terminals may lead to excitotoxic degeneration of Purkinje cells.
Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, MD 21205.
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O'Hearn
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Molliver
D000818:Animals; D064026:Calbindins; D002531:Cerebellum / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D006246:Harmaline / Q000633:toxicity*; D007050:Ibogaine / Q000633:toxicity*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000378:metabolism; D009410:Nerve Degeneration / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D009498:Neurotoxins / Q000633:toxicity*; D011689:Purkinje Cells / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D064030:S100 Calcium Binding Protein G / Q000032:analysis / Q000378:metabolism
D064026:Calbindins; D008869:Microtubule-Associated Proteins; D009498:Neurotoxins; D064030:S100 Calcium Binding Protein G; D007050:Ibogaine; D006246:Harmaline