Accumulating evidence indicates that general anesthetics can cause acute neuroapoptosis and long-term cognitive deficit in models exposed to anesthetics during the brain growth-spurt period. Anesthetics-induced imbalance of mitochondrial fusion and fission preceded and contributed to developmental neuroapoptosis. Accordingly, the imbalance was accompanied by activation of dynamin-related protein (Drp)1 which was closely associated with synaptic degeneration in neurodegenerative diseases. Based on the neuroprotective role of mitochondrial division inhibitor-1 (mdivi-1) in neurodegeneration and stroke, we set out to examine whether mdivi-1 can mitigate developmental neurotoxicity induced by isoflurane. In the present study, we showed that 2% isoflurane exposure for 2 h triggered Drp1 dephosphorylation at serine 656 and increased translocation of Drp1 and Bax from cytosol to mitochondria, concomitant with cytochrome C leakage into the cytosol. Remarkably, pretreatment with mdivi-1 not only alleviated isoflurane-induced disturbed mitochondrial translocation of Drp1 and Bax and almost restored morphological changes, but also inhibited cytochrome C release, caspase9 and caspase3 activation in hippocampi. Furthermore, mdivi-1 mitigated the loss of synaptic proteins and long-lasting cognitive deficit in later life of rats neonatally exposed to isoflurane. Taken together, isoflurane-induced Drp1 activation and translocation led to excessive mitochondrial fission and subsequently contributed to the synaptic injury and long-term cognitive impairment. However, mdivi-1 pretreatment prevented Drp1-dependent excessive mitochondrial fission and mitigated neuro-apoptosis and synaptic injury, and improved the long-term cognitive function. Thus mdivi-1 holds far-reaching insight for prophylaxis of developmental neurotoxicity induced by isoflurane.
Keywords: Bax; Drp1; Mdivi-1; isoflurane; mitochondria.