Methazolamide improves neurological behavior by inhibition of neuron apoptosis in subarachnoid hemorrhage mice

Abstract

Subarachnoid hemorrhage (SAH) results in significant nerve dysfunction, such as hemiplegia, mood disorders, cognitive and memory impairment. Currently, no clear measures can reduce brain nerve damage. The study of brain nerve protection after SAH is of great significance. We aim to evaluate the protective effects and the possible mechanism of methazolamide in C57BL/6J SAH animal model in vivo and in blood-induced primary cortical neuron (PCNs) cellular model of SAH in vitro. We demonstrate that methazolamide accelerates the recovery of neurological damage, effectively relieves cerebral edema, and improves cognitive function in SAH mice as well as offers neuroprotection in blood- or hemoglobin-treated PCNs and partially restores normal neuronal morphology. In addition, western blot analyses show obviously decreased expression of active caspase-3 in methazolamide-treated SAH mice comparing with vehicle-treated SAH animals. Furthermore, methazolamide effectively inhibits ROS production in PCNs induced by blood exposure or hemoglobin insult. However, methazolamide has no protective effects in morality, fluctuation of cerebral blood flow, SAH grade, and cerebral vasospasm of SAH mice. Given methazolamide, a potent carbonic anhydrase inhibitor, can penetrate the blood–brain barrier and has been used in clinic in the treatment of ocular conditions, it provides potential as a novel therapy for SAH.

Cerebroprotection by salvianolic acid B after experimental subarachnoid hemorrhage occurs via Nrf2- and SIRT1-dependent pathways

“…In our study, we first evaluated the antioxidant effects of SalB after SAH. Consistent with previous studies [5,58], ROS production was markedly induced in the early period after SAH. The overproduction of ROS triggered severe damage related to increased MDA levels and decreased antioxidant enzyme activity.…”

Nrf2 activation through the PI3K/GSK-3 axis protects neuronal cells from Aβ-mediated oxidative and metabolic damage

“…Underscoring the pharmacologic potential of the Aβprotective compounds employed in the current work for future prospective therapeutic strategies, it should be noted that both MTZ and MEL are FDA-approved drugs with well-studied bioavailability, organ distribution, and pharmacokinetics. As it is the case of Trolox, MTZ and MEL have been shown to be well-absorbed and cross the BBB [23,[118][119][120][121] and, as a result, have the potential to be active in vivo. Indeed, highlighting the relevance of our work and the potential of antioxidant treatment for neurodegenerative disorders, limited published work indicates that MEL administration preserved age-dependent cognitive impairment in APPPS1 transgenic mice [122] while Trolox protected this transgenic line from its characteristic neuritic alterations [123].…”

Cerebral influx of Na+ and Cl− as the osmotherapy-mediated rebound response in rats

“…In the present study, we therefore introduced a mixture of inhibitors targeting ion-transporting proteins expressed in the BBB capillary endothelium and/or the choroid plexus epithelium, and determined their effect on osmotherapy-induced brain ion accumulation. While amiloride and methazolamide may target abluminal ion-transporting mechanisms [ 21 , 42 ], we expect insignificant bumetanide interaction at the abluminal membrane of the capillaries forming the BBB because of its poor BBB permeability [ 43 , 44 ]. We failed to detect evidence in favor of NKCC1, NHE1, ENaC or carbonic anhydrase (indirectly targeting the bicarbonate transporters) located at the BBB endothelium or in choroid plexus participating in this brain volume regulation.…”