Mitochondria are involved in the neurogenic neuroprotection conferred by stimulation of cerebellar fastigial nucleus.
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.
Zhou
Ping
P
Division of Neurobiology, Weill Medical College of Cornell University, New York, NY 10021, USA. piz2001@med.cornell.edu
Qian
Liping
L
Zhou
Theresa
T
Iadecola
Costantino
C
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
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