JM-20 Treatment After MCAO Reduced Astrocyte Reactivity and Neuronal Death on Peri-infarct Regions of the Rat Brain

Abstract

Stroke is frequently associated with severe neurological decline and mortality, and its incidence is expected to increase due to aging population. The only available pharmacological treatment for cerebral ischemia is thrombolysis, with narrow therapeutic windows. Efforts aimed to identify new therapeutics are crucial. In this study, we look into plausible molecular and cellular targets for JM-20, a new hybrid molecule, against ischemic stroke in vivo. Male Wistar rats were subjected to 90 min middle cerebral artery occlusion (MCAO) following 23 h of reperfusion. Animals treated with 8 mg/kg JM-20 (p.o., 1 h after reperfusion) showed minimal neurological impairment and lower GABA and IL-1β levels in CSF when compared to damaged rats that received vehicle. Immunocontent of pro-survival, phosphorylated Akt protein decreased in the cortex after 24 h as result of the ischemic insult, accompanied by decreased number of NeuN cells in the peri-infarct cortex, cornu ammonis 1 (CA1) and dentate gyrus (DG) areas. Widespread reactive astrogliosis in both cortex and hippocampus (CA1, CA3, and DG areas) was observed 24 h post-ischemia. JM-20 prevented the activated Akt reduction, neuronal death, and astrocytes reactivity throughout the brain. Overall, the results reinforce the pharmacological potential of JM-20 as neuroprotective agent and provide important evidences about its molecular and cellular targets in this model of cerebral ischemia.

HMGB1-triggered inflammation inhibition of notoginseng leaf triterpenes against cerebral ischemia and reperfusion injury via MAPK and NF-κB signaling pathways

“…Researches exhibited that the inflammatory factors were induced not only in microglia of the CA1 region in the ischaemic hippocampus but also of the CA3 and DG regions [42,43], so the CA1 region and DG regions were further used to detect the inflammatory response [42,43,47,51,52].…”

Cerebrovascular Disease; A Leading Cause of Epilepsy

“…Histological changes immediately after stroke are reported by Ramírez-Sánchez et al [96]. When rats were subjected to 90 minutes MCA occlusion followed by 23 hours of reperfusion, neuronal cells in the peri-infart cortex, cornu ammonis (CA) 1, and dentate gyrus (DG) areas were decreased, and widespread reactive astrogliosis in both of the cortex and the hippocampus (CA1, CA3, and DG areas) was observed 24 hours after ischemia.…”

Preventive and therapeutic effects of JM-20 on paclitaxel-evoked painful peripheral neuropathy in rats

“…JM-20 prevents the Ca 2+ -induced mitochondrial permeability transition, as assessed by mitochondrial swelling, potential membrane dissipation, and organelle release of the pro-apoptotic protein cytochrome c in rat liver and brain mitochondria (Nuñez-Figueredo et al, 2014b). Nevertheless, since neuropathy induced by paclitaxel involves a strong peripheral and central inflammatory component, the ability of JM-20 to decrease the peripheral neuroinflammatory reaction, as well as to inhibit glial activation and apoptotic cell signaling pathways, could also involve in its preventive effect (Boyette-Davis et al, 2015;Ramírez-Sánchez et al, 2015;2018;Garrido-Suárez et al, 2020). JM-20 can decrease plasma extravasation and tumor necrosis factor-alpha production in the inflammatory model (Garrido-Suárez et al, 2020).…”

“…It is based on a multimodal drug design paradigm for cerebrovascular disease (Nuñez-Figueredo et al, 2013). This molecule possesses GABAergic activity and a robust neuroprotective ability, as demonstrated in models relevant to cerebral ischemia and related to anti-excitotoxic, anti-inflammatory, anti-apoptotic, mitoprotective, and antioxidant effects (Nuñez-Figueredo et al, 2013;2014a;2014b;2014c;Ramírez-Sánchez et al, 2015;2018). Recently, JM-20 decreases chronic constriction injury (CCI)-induced mechanical hypersensitivity in relation to its preventive effect on Wallerian degeneration (WD), has been reported (Garrido-Suárez et al, 2020).…”