esculetin and Cognitive-Dysfunction

To investigate the effects of different doses of esculetin on epileptiform activity, behavioral seizures, memory impairment, and cortical and hippocampal NF-κB, as a mediator of pro-inflammatory gene induction, and pro-inflammatory cytokines in penicillin- and pentylenetetrazole(PTZ)-induced seizure models in rats.. Different doses of esculetin (5, 10, and 20 mg/kg), and diazepam (5 mg/kg) as a positive control, were tested in penicillin- and pentylenetetrazole(PTZ)-induced seizure models. In the PTZ model, cognitive function, behavioral seizures, and cortical and hippocampal pro-inflammatory biomarkers and survival factor was evaluated. In the penicillin model, the frequency and amplitude of electrophysiological epileptiform activity were assessed.. In the PTZ model, the 10 mg/kg esculetin displayed anticonvulsant effects by extending onset-times of myoclonic-jerk and generalized tonic-clonic seizure, and by diminishing seizure severity and duration of generalized tonic-clonic seizure. It also ameliorated PTZ-induced cognitive impairment, and cortical and hippocampal activin-A, IL-1β, IL-6 and NF-κB levels. In the penicillin model, the 10 mg/kg esculetin decreased the frequency of spikes without changing the amplitude of spikes. As a positive-control, diazepam reversed all changes induced by both PTZ and penicillin.. Esculetin exhibits anticonvulsant and memory-improving effects by alleviating the behavioral and electrophysiological characteristics of epileptic seizures. Additionally, esculetin exerts anti-neuroinflammatory actions in the PTZ-induced seizures model. Thus, esculetin may be a multi-targeted promising agent with anticonvulsant and anti-neuroinflammatory effects in the treatment of epilepsy.

Topics: Animals; Anticonvulsants; Cognitive Dysfunction; Cytokines; Diazepam; Disease Models, Animal; Epilepsy; NF-kappa B; Pentylenetetrazole; Rats; Seizures

Mitochondrial dynamics regulate mitochondrial autophagy (mitophagy) and apoptosis, which are important events for the quality control of mitochondria and mitochondrial-associated diseases. Esculetin (ESC) is a natural coumarin that exhibits inspiring biological activities in a variety of animal models, but its neuroprotective effects on cerebral ischaemia have not been clearly elucidated. In this paper, we demonstrated the effects of ESC on transient cerebral ischaemia and reperfusion injury induced in a mouse model and examined the possible underlying mechanisms by investigating mitochondrial fragmentation-regulated mitochondrial autophagy and apoptosis. The experimental results showed that ESC treatment alleviated neurological defects and improved cognitive impairments in transient bilateral common carotid artery occlusion (tBCCAO)-treated mice. Further mechanism studies showed that tBCCAO induced mitochondrial oxidative stress injuries and triggered mitochondrial fragmentation, which were evident by the elevated levels of malondialdehyde and mitochondrial dynamin-related protein 1 (Drp1) and the downregulated activities of superoxide dismutase and nuclear transcription factor E2-related factor 2 (Nrf2). ESC treatment significantly alleviated tBCCAO-induced mitochondrial stress and mitochondrial fragmentation. Moreover, mitophagy and mitochondrial apoptosis were stimulated in response to the mitochondrial oxidative stress in the hippocampus of tBCCAO-treated mice, and ESC treatment regulated the expression of mitophagy-related factors, including Bnip3, Beclin1, Pink1, and parkin, the LC-3 II/I ratio, and apoptosis-related factors, including p53, Bax, and caspase 3. Taken together, our results suggest that ESC treatment regulated hippocampal mitophagy and mitochondrial apoptosis triggered by mitochondrial stress via the mediation of mitochondrial fragmentation during transient cerebral ischaemia and reperfusion injury, which provides insight into the potential of ESC for further therapeutic implications.

Topics: Animals; Apoptosis; Autophagy; Brain Ischemia; Cognitive Dysfunction; Dynamins; Ischemic Attack, Transient; Male; Malondialdehyde; Mice; Mice, Inbred ICR; Mitochondria; Mitophagy; NF-E2-Related Factor 2; Reactive Oxygen Species; Reperfusion Injury; Superoxide Dismutase; Umbelliferones