(+)-Borneol exerts neuroprotective effects via suppressing the NF-κB pathway in the pilocarpine-induced epileptogenesis rat model.

Neuroinflammation plays a crucial role in the development of epilepsy, and suppressing neuroinflammation can delay epileptogenesis. Recent reports have demonstrated that (+)-borneol has neuroprotective effects in several brain disorders by reducing neuroinflammation. However, its effects on epilepsy have not been reported. In this research, we first studied the effect of different doses of (+)-borneol (3, 6, and 12 mg/kg) on neuroinflammation in a pilocarpine model of epileptogenesis by detecting IL-1ß, TNF-α, and COX-2 expression. We demonstrated that different doses of (+)-borneol decreased IL-1ß, TNF-α, and COX-2 levels, with 12 mg/kg having the most substantial effect. Furthermore, we examined the effects of 12 mg/kg (+)-borneol on neuronal damage, glial cell activation, and apoptosis in the hippocampus at different time points (1, 3, and 7 days) after SE. We found that (+)-borneol significantly ameliorated neuronal injury, decreased glial cell activation, and attenuated apoptosis. We also found that (+)-borneol inhibited the NF-κB pathway activation induced by SE. In conclusion, our results indicated that (+)-borneol reduces neuroinflammation by inhibiting the NF-κB pathway activation, exerts neuroprotective effects, and may have an inhibitory effect in epileptogenesis.

Amifostine ameliorates cerebral ischaemia-reperfusion injury via p38-mediated oxidative stress and mitochondrial dysfunction.

Amifostine is a cytoprotective compound that is beneficial in ischaemic stroke cases. However, the neuroprotective effect of amifostine on ischaemia/reperfusion (I/R)-induced brain injury and its underlying mechanism are still poorly understood. Herein, we constructed an animal model of middle cerebral artery occlusion and reperfusion (MCAO/R) injury and an in vitro model of oxygen and glucose deprivation and reperfusion (OGD/R) injury. After administration of amifostine, we found significant improvements in neurological deficits, infarct size, and cerebral oedema. Moreover, amifostine alleviated histopathological alteration and increased the number of surviving neurons. Biochemical analysis showed that treatment with amifostine obviously improved the brain damage of MCAO/R mice, as manifested by a decrease in reactive oxygen species (ROS) and malondialdehyde (MDA) generation, and an increase in superoxide dismutase (SOD) activity. Moreover, amifostine decreased the mitochondrial membrane potential (m) loss, and cytochrome c escaping to cytoplasm, but increased the ATP level. In vitro, amifostine also showed an antioxidant effect, which was reflected by the reduced ROS generation, decreased mitochondrial superoxide generation, increased total SOD, SOD1 (Cu/Zn SOD, cytoplasmic SOD), and SOD2 (mitochondrial SOD) activities, and decreased m loss. Furthermore, amifostine suppressed neuronal apoptosis, accompanied by the reduction of Bax, cleaved caspase-9, cleaved caspase-3, and Bcl-2 upregulation. Amifostine also reduced the expression of p-p38 (Thr 180/Tyr 182) in vivo and in vitro. In short, amifostine exhibits a protective effect on cerebral I/R damage through modulating p38-related oxidative stress, mitochondrial dysfunction, and apoptosis.

The novel GLP-1/GIP dual receptor agonist DA3-CH is neuroprotective in the pilocarpine-induced epileptogenesis rat model.

AIMS: Glia-mediated neuro-inflammation and oxidative stress-induced neuronal apoptosis can contribute to epileptogenesis. We have demonstrated previously that mimetics of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and dual-GLP-1/GIP receptor agonists protect the brain from inflammation, oxidative stress, apoptosis and neuronal loss in animal models of central nervous system diseases. METHODS: This study investigated for the first time whether the novel dual GLP-1/GIP receptor agonist DA3-CH has neuroprotective effects in the pilocarpine-induced status epilepticus (SE) rat model and the studies the underlying mechanisms. DA3-CH was administered once daily at 10 nmol/kg ip. following SE induction. The effect of DA3-CH was evaluated by immunohistochemistry and western blot at 12 h, 1 d, 3 d, 7 d after kindling. RESULTS: Our findings show that DA3-CH reduced the chronic inflammation response (astrogliosis and microgliosis), and the associated release of the pro-inflammatory cytokines interleukin-1ß (IL-ß) and tumor necrosis factor-α (TNF-α) in the hippocampal CA1 area. Furthermore, DA3-CH reduced the expression of the mitochondrial pro-apoptotic protein Bax, while increasing the expression of the anti-apoptotic protein Bcl-2. Neuronal numbers in the CA1 area were much reduced by pilocarpine treatment, and DA3-CH protected neurons from neurotoxicity. CONCLUSION: These results demonstrated that DA3-CH could mitigate pilocarpine-induced neuro-inflammation, mitochondrial apoptosis and neuronal loss. The findings encourage the development of dual agonists as novel therapeutic interventions for epilepsy.