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Sodium valproate (VPA) is a broad-spectrum anticonvulsant that is effective both in adults and children suffering from epilepsy, but it causes psychiatric and behavioral side effects in patients with epilepsy. In addition, 30% of patients with epilepsy develop resistance to VPA. At present, regular physical exercise has shown many benefits and has become an effective complementary therapy for various brain diseases, including epilepsy. Therefore, we wondered whether VPA combined with exercise would be more effective in the treatment of seizures and associated co-morbidities. Here, we used a mouse model with kainic acid (KA)-induced epilepsy to compare the seizure status and the levels of related co-morbidities, such as cognition, depression, anxiety, and movement disorders, in each group using animal behavioral experiment and local field potential recordings. Subsequently, we investigated the mechanism behind this phenomenon by immunological means. Our results showed that low-intensity exercise combined with VPA reduced seizures and associated co-morbidities. This phenomenon seems to be related to the Toll-like receptor 4, activation of the nuclear factor kappa B (NF-κB), and release of interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), and IL-6. In brief, low-intensity exercise combined with VPA enhanced the downregulation of NF-κB-related inflammatory response, thereby alleviating the seizures, and associated co-morbidities.

Brain disorders, including stroke, Alzheimer's disease, depression, and chronic pain, are difficult to effectively treat. These major brain disorders have high incidence and mortality rates in the general population, and seriously affect not only the patient's quality of life, but also increases the burden of social medical care. Aerobic physical exercise is considered an effective adjuvant therapy for preventing and treating major brain disorders. Although the underlying regulatory mechanisms are still unknown, systemic processes may be involved. Here, this review aimed to reveal that aerobic physical exercise improved depression and several brain functions, including cognitive functions, and provided chronic pain relief. We concluded that aerobic physical exercise helps to maintain the regulatory mechanisms of brain homeostasis through anti-inflammatory mechanisms and enhanced synaptic plasticity and inhibition of hippocampal atrophy and neuronal apoptosis. In addition, we also discussed the cross-system mechanisms of aerobic exercise in regulating imbalances in brain function, such as the “bone-brain axis.” Furthermore, our findings provide a scientific basis for the clinical application of aerobic physical exercise in the fight against brain disorders.

The gene kcnma1 encodes the α-subunit of high-conductance calcium- and voltage-dependent K+ (BK) potassium channel. With the development of generation gene sequencing technology, many KCNMA1 mutants have been identified and are more closely related to generalized epilepsy and paroxysmal dyskinesia. Here, we performed a genetic screen of 26 patients with febrile seizures and identified a novel mutation of KCNMA1 (E155Q). Electrophysiological characterization of different KCNMA1 mutants in HEK 293T cells, the previously-reported R458T and E884K variants (not yet determined), as well as the newly-found E155Q variant, revealed that the current density amplitude of all the above variants was significantly smaller than that of the wild-type (WT) channel. All the above variants caused a positive shift of the I-V curve and played a role through the loss-of-function (LOF) mechanism. Moreover, the β4 subunit slowed down the activation of the E155Q mutant. Then, we used kcnma1 knockout (BK KO) mice as the overall animal model of LOF mutants. It was found that BK KO mice had spontaneous epilepsy, motor impairment, autophagic dysfunction, abnormal electroencephalogram (EEG) signals, as well as possible anxiety and cognitive impairment. In addition, we performed transcriptomic analysis on the hippocampus and cortex of BK KO and WT mice. We identified many differentially expressed genes (DEGs). Eight dysregulated genes [i.e., (Gfap and Grm3 associated with astrocyte activation) (Alpl and Nlrp10 associated with neuroinflammation) (Efna5 and Reln associated with epilepsy) (Cdkn1a and Nr4a1 associated with autophagy)] were validated by RT-PCR, which showed a high concordance with transcriptomic analysis. Calcium imaging results suggested that BK might regulate the autophagy pathway from TRPML1. In conclusion, our study indicated that newly-found point E155Q resulted in a novel loss-of-function variant and the dysregulation of gene expression, especially astrocyte activation, neuroinflammation and autophagy, might be the molecular mechanism of BK-LOF meditated epilepsy.

Objecive: To investigate the efficacy and mechanisms of Dingxian pill combined with valproic acid (VPA) on pentylenetetrazol-induced chronical epilepsy in rats., Methods: A rat model of epilepsy was established by administering pentylenetetrazol (PTZ) water solution (35 mg/kg). Rats were divided into 4 groups, among which three groups were treated with different drugs once a day for 28 d including Dingxian pill (2.4 g/kg), VPA (0.2 g/kg), or a combination of Dingxian pill (2.4 g/kg) and VPA (0.2 g/kg) respectively, and the control group was given the same volume of saline. Rats in different groups were compared based on animal behavior, electroencephalograms, Morris water maze, immunohistochemistry, transcriptomics and real-time polymerase chain reaction., Rsults: The combination therapy of Dingxian pill and VPA inhibited PTZ-induced seizure-like behavior and reduced seizure grades more significantly than VPA alone. Compared with the control group, the learning and memory ability of chronic PTZ-induced epileptic rats was improved in all the drug treatment groups, especially in the group that received both Dingxian pill and VPA. Similar to the results of MWM tests, expression of the neuroexcitability marker gene c-Fos was reduced after Dingxian pill and/or VPA treatment, and the effect was most pronounced in the combined treatment group. Transcriptomic analysis revealed that gene expression in the rodent hippocampus, which is involved in epilepsy, was upregulated by combined treatment with Dingxian pill and VPA, compared with VPA treatment alone., Conclusion: Our results not only highlight the anti-epileptic effects of combined Dingxian pill and VPA treatment, but also shed light on the underlying molecular mechanisms and provide a way to apply Traditional Chinese Medicine in the treatment of epilepsy.