title: Mitochondria are involved in the neurogenic neuroprotection conferred by stimulation of cerebellar fastigial nucleus.
abstract: Activation of neural pathways originating in the cerebellar fastigial nucleus (FN) protects the brain from the deleterious effects of cerebral ischemia and excitotoxicity, a phenomenon termed central neurogenic neuroprotection. The neuroprotection is, in part, mediated by suppression of apoptosis. We sought to determine whether FN stimulation exerts its anti-apoptotic effect through mitochondrial mechanisms. Mitochondria were isolated from the cerebral cortex of rats in which the FN was stimulated for 1 h (100 microA; 1 s on/1 s off), 72 h earlier. Stimulation of the dentate nucleus (DN), a brain region that does not confer neuroprotection, served as control. Mitochondria isolated from FN-stimulated rats exhibited a marked increase in their ability to sequester Ca2+ and an increased resistance to Ca2+-induced membrane depolarization and depression in respiration. FN stimulation also leads to reduction in the release in cytochrome c, induced either by Ca2+ or the mitochondrial toxin mastoparan. Furthermore, in brain slices, FN stimulation reduced the staurosporine-induced insertion of the pro-apoptotic protein Bax into the mitochondria, a critical step in the mitochondrial mechanisms of apoptosis. Collectively, these results provide evidence that FN stimulation protects the mitochondria from dysfunction induced by Ca2+ loading, and inhibits mitochondrial pathways initiating apoptosis. These mitochondrial mechanisms are likely to play a role in the neuroprotection exerted by FN stimulation.
authors.affiliation: Division of Neurobiology, Weill Medical College of Cornell University, New York, NY 10021, USA. piz2001@med.cornell.edu
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.forename: Liping
authors.initials: L
authors.lastname: Qian
authors.forename: Theresa
authors.initials: T
authors.lastname: Zhou
authors.forename: Costantino
authors.initials: C
authors.lastname: Iadecola
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002529:Cerebellar Nuclei / Q000502:physiology*; D002540:Cerebral Cortex / Q000378:metabolism / Q000502:physiology*; D045304:Cytochromes c / Q000037:antagonists & inhibitors / Q000378:metabolism; D004558:Electric Stimulation; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins; D007425:Intracellular Membranes / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D010101:Oxygen Consumption / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014862:Wasp Venoms / Q000494:pharmacology; D051028:bcl-2-Associated X Protein
chemical_list: C494828:Bax protein, rat; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D014862:Wasp Venoms; D051028:bcl-2-Associated X Protein; C037500:mastoparan; D045304:Cytochromes c; D002118:Calcium