Nimodipine is an L type calcium channel antagonist that

Nimodipine is an L-type calcium channel antagonist that reduces excessive calcium influx during pathological conditions, contributing to its neuroprotective properties (Zornow and Prough, 1996; Kobayashi and Mori, 1998). Autophagy can be induced by increased [Ca2+] (Rami et al., 2008). Nimodipine significantly decreases [Ca2+] at 24 h following reoxygenation. While it is largely unknown about the effect of nimodipine on energy metabolism and autophagy induced by CCH. Herein, we demonstrated that the AMPK phosphorylation activated the eIF2α/ATF4 pathway to promote autophagy after CCH.
Material and methods
Results
Discussion Nimodipine administration inhibited the level of AMP-activated protein kinase (AMPK) phosphorylation, a sensor of cellular energy status that directs metabolic Retapamulin to support cellular growth and survival. CCH influences the oxygen and glucose supply in the brain which often results in metabolic alterations and oxidative stress. A variety of signaling molecules have been found to regulate metabolism in response to distinct metabolic stress (Paiva et al., 2011). And AMPK has been extensively demonstrated as an important metabolic regulator activated during hypoxia, oxidative, stress, glucose deprivation, and ischemia. AMPK responds to changes in intracellular adenine nucleotide levels, being activated by an increase in AMP/ADP relative to ATP. Activation of AMPK increases the rate of catabolic (ATP generating) pathways and decreases the rate of anabolic (ATP utilising) pathways (Carling, 2017). And phosphorylates TSC1/2 to activate autophagy (Simon et al., 2017). Since phosphorylation stimulates the catalytic activity of AMPK (Gwinn et al., 2008), the increased relative levels of p-AMPK suggested that AMPK was activated in the hippocampus of 2VO rats. In mammals, calcium/calmodulin dependent protein kinase kinase (CaMKK) β and liver kinase B1 (LKB1) have been identified as the two upstream kinases in the cascade (Woods et al., 2005; Woods et al., 2003). Intracellular calcium was increased in cerebral hypufusion rats (Min et al., 2013). That increase intracellular Ca2+ activate AMPK via phosphorylation of Thr172 by the calmodulin-dependent protein kinase CaMKKb (Woods et al., 2005). Nimodipine, an L-type calcium channel antagonist, inhibited intracellular Ca2+ generation. Hence, Nimodipine administration inhibited excessive autophagy by decreasing the level of AMPK phosphorylation. Cerebral hypofusion may bring a potent cellular stress, in which AMPK phosphorylation triggers autophagy. Autophagy is induced during different stress responses, including starvation, oxidative stress and hypoxia (Rami et al., 2008; Yang et al., 2014) and is associated with the pathological mechanisms involved in many diseases. The presence of autophagosomes in dying cells has implicated autophagy in the cell death process. Indeed, excessive autophagic activity may destroy portions of the cytosol and organelles, leading to a collapse of all cellular functions. Studies have confirmed that autophagy activated in the hippocampus of VaD induced by cerebral hypofusion (Liu et al., 2014). Autophagy dysfunction occurred early after CCH and played an important role in neuronal deterioration and cognitive decline (Zou et al., 2017). Activation of autophagy initiation remained elevated beginning at 2 weeks after 2VO in the cortex and at 4 weeks in the hippocampus, and autophagy played an important role in the processes of neuronal injury and cognitive decline (Zou et al., 2017). In the present study, autophagy is markedly activated along with neuronal deterioration, cognitive decline after 5 weeks of 2VO. LC3B, a microtubule-associated protein that is lipidated upon activation of autophagy (Jiwa et al., 2010). Moreover, one study reported that in cerebral hypofusion rat, the induction of autophagy was linked to the localization of LC3B in dystrophic axons. Nimodipine significantly decreased autophagy after 4 weeks of administration consistent with the reduced p-AMPK aggregation. Meanwhile, neuronal degeneration in the nimodipine group was significantly improved. These findings indicate that nimodipine may modulate energy sensing AMPK to reduce excessive autophagy and protect hippocampal neurons form degeneration induced by 2VO.