Melatonin‐enhanced autophagy protects against neural apoptosis via a mitochondrial pathway in early brain injury following a subarachnoid hemorrhage

Abstract

Melatonin is a strong antioxidant that has beneficial effects against early brain injury (EBI) following a subarachnoid hemorrhage (SAH) in rats; protection includes reduced mortality and brain water content. The molecular mechanisms underlying these clinical effects in the SAH model, however, have not been clearly identified. This study was undertaken to determine the influence of melatonin on neural apoptosis and the potential mechanism of these effects in EBI following SAH using the filament perforation model of SAH in male Sprague Dawley rats. Melatonin (150 mg/kg) or vehicle was given via an intraperitoneal injection 2 hr after SAH induction. Brain samples were extracted 24 hr after SAH. The results show that melatonin treatment markedly reduced caspase-3 activity and the number of TUNEL-positive cells, while the treatment increased the LC3-II/LC3-I, an autophagy marker, which indicated that melatonin-enhanced autophagy ameliorated apoptotic cell death in rats subjected to SAH. To further identify the mechanism of autophagy protection, we demonstrated that melatonin administration reduced Bax translocation to the mitochondria and the release of cytochrome c into the cytosol. Taken together, this report demonstrates that melatonin improved the neurological outcome in rats by protecting against neural apoptosis after the induction of filament perforation SAH; moreover, the mechanism of these antiapoptosis effects was related to the enhancement of autophagy, which ameliorated cell apoptosis via a mitochondrial pathway.

Minocycline Protects Against NLRP3 Inflammasome-Induced Inflammation and P53-Associated Apoptosis in Early Brain Injury After Subarachnoid Hemorrhage

“…The endovascular perforation SAH rat model was produced as previously described with modifications [24]. Briefly, after the rats were anesthetized with an intraperitoneal injection of pentobarbital (40 mg/kg), the left carotid artery and its branches were exposed.…”

“…Western blot analysis was performed as previously described [24]. The cytoplasmic and nuclear protein extracts were prepared with the NE-PER nuclear and cytoplasmic extraction reagents (Thermo, Rockford, IL, USA) according to the manufacturer's instructions.…”

Promising Role of Melatonin as Neuroprotectant in Neurodegenerative Pathology

“…Melatonin treatment also inhibits the rotenone-induced impaired neuromuscular coordination, neuronal death, and DNA damage [81,82]. It attenuates apoptosis and oxidative stress in neurons and mesenchymal stem cells by upregulating the antiapoptotic protein bcl-2 [83,84]. It also alters the cell death processes in response to age-related oxidative stress and apoptosis in the brain of senescenceaccelerated mice [85].…”

“…Recent studies have showed the antiapoptotic property of melatonin in rodent brain and in cell culture studies. Melatonin attenuates the neuron apoptosis in hippocampus and oxidative stress during chronic intermittent hypoxia [83]. It inhibits the β-amyloid generation and cholinergic dysfunction in the hippocampus of aged rats by its antiapoptotic effects [95].…”

Ethyl pyruvate alleviates early brain injury following subarachnoid hemorrhage in rats

“…Western blot analysis was performed as previously described [7]. Briefly, the left basal cortical sample was homogenized and centrifuged at 1000 g for 10 min at 4°C.…”