PGC-1α Affects Epileptic Seizures by Regulating Mitochondrial Fusion in Epileptic Rats.

BACKGROUND: Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), regulated by AMPK, is an important regulator of mitochondrial fusion. At present, whether the AMPK/PGC-1α signaling pathway regulates mitochondrial dynamics in epileptic rats is still unknown. METHODS: Adult male Sprague-Dawley (SD) rats were randomly divided into fourgroups: the control group (0.9% saline, n = 5), the EP groups (lithium-pilocarpine was used to induce epilepsy, and tissues were harvested at 6 and 24 h, every time point, n = 5), the EP + Compound C group (the specific inhibitor of PGC-1α, 15 mg/kg in 2% DMSO, n = 5), and the EP + DMSO group (0.9% saline + 2% DMSO, n = 5). To investigate whether PGC-1α participates in seizures by regulating the expression of mitofusin1/2(MFN1/2)in rats. RESULTS: In this study, the behavioral results indicate that the seizure susceptibility of the rats to epilepsy was increased when the expression of PGC-1α was inhibited. Subsequently, Western blot results suggested that the expression level of both MFN1 and MFN2 in the hippocampus was higher at 6 and 24 h after an epileptic seizure. Besides, the expression of PGC-1α and MFN2 was significantly decreased in the hippocampus when the epileptic rats were treated with Compound C. Furthermore, the immunofluorescence analysis of the localization of MFN1/2 and PGC-1α showed that MFN1/2 was mainly expressed in neurons but not astrocytes in the hippocampus and cerebral cortex of rats. Meanwhile, PGC-1α colocalized with the excitatory post-synaptic marker PSD95, suggesting that PGC-1α may regulate the seizure susceptibility of the rats by mediating excitatory post-synaptic signaling. CONCLUSION: The AMPK/PGC-1α signaling pathway may play an important role in the lithium-pilocarpine-induced epileptic rat model by mediating the expression of fusion proteins.

The mechanism of mitochondrial autophagy regulating Clathrin-mediated endocytosis in epilepsy.

OBJECTIVE: The objective of this study is to determine whether inhibition of mitophagy affects seizures through Clathrin-mediated endocytosis (CME). METHODS: Pentylenetetrazol (PTZ) was intraperitoneally injected daily to establish a chronic PTZ-kindled seizure. The Western blot (WB) was used to compare the differences in Parkin protein expression between the epilepsy group and the control group. Immunofluorescence was used to detect the expression of MitoTracker and LysoTracker. Transferrin-Alexa488 (Tf-A488) was injected into the hippocampus of mice. We evaluated the effect of 3-methyladenine (3-MA) on epilepsy behavior through observation in PTZ-kindled models. RESULTS: The methylated derivative of adenine, known as 3-MA, has been extensively utilized in the field of autophagy research. The transferrin protein is internalized from the extracellular environment into the intracellular space via the CME pathway. Tf-A488 uses a fluorescent marker to track CME. Western blot showed that the expression of Parkin was significantly increased in the PTZ-kindled model (p < 0.05), while 3-MA could reduce the expression (p < 0.05). The fluorescence uptake of MitoTracker and LysoTracker was increased in the primary cultured neurons induced by magnesium-free extracellular fluid (p < 0.05); the fluorescence uptake of Tf-A488 was significantly decreased in the 3-MA group compared with the control group (p < 0.05). Following hippocampal injection of Tf-A488, both the epilepsy group and the 3-MA group exhibited decreased fluorescence uptake, with a more pronounced effect observed in the 3-MA group. Inhibition of mitophagy by 3-MA from day 3 to day 9 progressively exacerbated seizure severity and shortened latency. SIGNIFICANCE: It is speculated that the aggravation of seizures by 3-MA may be related to the failure to remove damaged mitochondria in time and effectively after inhibiting mitochondrial autophagy, affecting the vesicle endocytosis function of CME and increasing the susceptibility to epilepsy. SUMMARY: Abnormal mitophagy was observed in a chronic pentylenetetrazol-induced seizure model and a Mg2+-free-induced spontaneous recurrent epileptiform discharge model. A fluorescent transferrin marker was utilized to track clathrin-mediated endocytosis. Using an autophagy inhibitor (3-methyladenine) on primary cultured neurons, we discovered that inhibition of autophagy led to a reduction in fluorescent transferrin uptake, while impairing clathrin-mediated endocytosis function mediated by mitophagy. Finally, we examined the effects of 3-methyladenine in an animal model of seizures showing that it exacerbated seizure severity. Ultimately, this study provides insights into potential mechanisms through which mitophagy regulates clathrin-mediated endocytosis in epilepsy.

Phosphoglycerate kinase (PGK) 1 succinylation modulates epileptic seizures and the blood-brain barrier.

Epilepsy is the most common chronic disorder in the nervous system, mainly characterized by recurrent, periodic, unpredictable seizures. Post-translational modifications (PTMs) are important protein functional regulators that regulate various physiological and pathological processes. It is significant for cell activity, stability, protein folding, and localization. Phosphoglycerate kinase (PGK) 1 has traditionally been studied as an important adenosine triphosphate (ATP)-generating enzyme of the glycolytic pathway. PGK1 catalyzes the reversible transfer of a phosphoryl group from 1, 3-bisphosphoglycerate (1, 3-BPG) to ADP, producing 3-phosphoglycerate (3-PG) and ATP. In addition to cell metabolism regulation, PGK1 is involved in multiple biological activities, including angiogenesis, autophagy, and DNA repair. However, the exact role of PGK1 succinylation in epilepsy has not been thoroughly investigated. The expression of PGK1 succinylation was analyzed by Immunoprecipitation. Western blots were used to assess the expression of PGK1, angiostatin, and vascular endothelial growth factor (VEGF) in a rat model of lithium-pilocarpine-induced acute epilepsy. Behavioral experiments were performed in a rat model of lithium-pilocarpine-induced acute epilepsy. ELISA method was used to measure the level of S100ß in serum brain biomarkers' integrity of the blood-brain barrier. The expression of the succinylation of PGK1 was decreased in a rat model of lithium-pilocarpine-induced acute epilepsy compared with the normal rats in the hippocampus. Interestingly, the lysine 15 (K15), and the arginine (R) variants of lentivirus increased the susceptibility in a rat model of lithium-pilocarpine-induced acute epilepsy, and the K15 the glutamate (E) variants, had the opposite effect. In addition, the succinylation of PGK1 at K15 affected the expression of PGK1 succinylation but not the expression of PGK1total protein. Furthermore, the study found that the succinylation of PGK1 at K15 may affect the level of angiostatin and VEGF in the hippocampus, which also affects the level of S100ß in serum. In conclusion, the mutation of the K15 site of PGK1 may alter the expression of the succinylation of PGK1 and then affect the integrity of the blood-brain barrier through the angiostatin / VEGF pathway altering the activity of epilepsy, which may be one of the new mechanisms of treatment strategies.

Facial-onset sensory and motor neuronopathy with myasthenia gravis: A case report.

RATIONALE: Facial-onset sensory and motor neuronopathy (FOSMN) is a greatly rare disease, so far, autopsy evidence that is associated with neurodegenerative. Myasthenia gravis (MG) is an antibody-mediated and complement-involved acquired autoimmune disorder of the post-synaptic neuromuscular junction. There have been few reports about if there is related between the 2. In this study, we present the case of a man who was diagnosed as FOSMN with MG in continuity. PATIENT CONCERNS: The patient chief complaints were right-side facial numbness and right-eyelid incomplete closure, followed by slurred speech and dysphagia, and the symptoms gradually progressed. The patient serum was positive for anti-AchR and anti-Titin antibodies. DIAGNOSES: The patient was diagnosed FOSMN with MG. INTERVENTIONS: The patient symptoms were relieved after pyridostigmine bromide and prednisolone treatment. OUTCOMES: Symptoms have improved. LESSONS: Facial-onset sensory and motor neuronopathy and MG have disparate clinical features. Therefore, we reported a rare case in which the 2 conditions concurrently existed. Immune dysfunction might be the pathogenesis of this association, while there is no definite evidence to support it, further studies are needed.

When herpes simplex virus encephalitis meets antiviral innate immunity.

Herpes simplex virus (HSV) is the most common pathogen of infectious encephalitis, accounting for nearly half of the confirmed cases of encephalitis. Its clinical symptoms are often atypical. HSV PCR in cerebrospinal fluid is helpful for diagnosis, and the prognosis is usually satisfactory after regular antiviral treatment. Interestingly, some patients with recurrent encephalitis have little antiviral effect. HSV PCR in cerebrospinal fluid is negative, but glucocorticoid has a significant effect after treatment. Specific antibodies, such as the NMDA receptor antibody, the GABA receptor antibody, and even some unknown antibodies, can be isolated from cerebrospinal fluid, proving that the immune system contributes to recurrent encephalitis, but the specific mechanism is still unclear. Based on recent studies, we attempt to summarize the relationship between herpes simplex encephalitis and innate immunity, providing more clues for researchers to explore this field further.

Research progress on correlations between trace element levels and epilepsy.

Research investigating the correlation between human trace element levels and disease alterations is growing. Epilepsy, a common nervous system disease, has also been found to be closely related to abnormal levels of trace elements. Studies continue to explore mechanisms of various trace elements involved in epileptic seizures through experimental animal models of epilepsy. Thus, we reviewed the research progress on the correlation between trace element levels and epilepsy in recent years and found that the trace elements most closely related to epilepsy are mainly metal ions such as selenium, iron, copper, zinc, and manganese. These results indicate that the changes in some trace elements are closely related to the increase in epilepsy susceptibility. In addition, after treatment with drugs and a ketogenic diet, the concentration of trace elements in the serum of patients with epilepsy changes. In other words, the abnormality of trace element concentrations is of great significance in the occurrence and development of epilepsy. This article is a literature update on the potential role of trace element imbalance in the development of epilepsy, providing new references for the subsequent prevention and treatment of epilepsy.

Gut Microbes Regulate Innate Immunity and Epilepsy.

Epilepsy is a common chronic brain disease. There are many clinical methods to control epileptic seizures, such as anti-seizure medications (ASMs) or surgical removal of epileptogenic lesions. However, the pathophysiology of epilepsy is still unknown, making it difficult to control or prevent it. The host's immune system monitors gut microbes, interacts with microbes through pattern recognition receptors such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs) expressed by innate immune cells, and activates immune responses in the body to kill pathogens and balance the relationship between microbes and host. In addition, inflammatory responses induced by the innate immune system are seen in animal models of epilepsy and temporal lobe epilepsy brain tissue to combat pathogens or injuries. This review summarizes the potential relationship between gut microbes, innate immunity, and epilepsy based on recent research to provide more hints for researchers to explore this field further.

Management of anti-seizure medications in lactating women with epilepsy.

Epilepsy is a common neurological disease. At present, there are about 70 million epilepsy patients in the world, half of them are women, and 30-40% of women with epilepsy are of childbearing potential. Patients with epilepsy who are of childbearing potential face more challenges, such as seizures caused by hormonal fluctuations and the risk of adverse effects on the mother and baby from taking anti-seizure medications (ASMs). Breast milk is one of the best gifts that a mother can give her baby, and breastfeeding can bring more benefits to the baby. Compared with healthy people, people with epilepsy have more concerns about breastfeeding because they are worried that ASMs in their milk will affect the growth and development of the baby, and they are always faced with the dilemma of whether to breastfeed after childbirth. Regarding, whether women with epilepsy can breastfeed while taking ASMs, and whether breastfeeding will adversely affect the baby is still an important topic of concern for patients and doctors. This article reviews the existing research on breastfeeding-related issues in women with epilepsy to guide clinical practice, and improve the breastfeeding compliance of women with epilepsy.

Research Progress on the Effect of Epilepsy and Antiseizure Medications on PCOS Through HPO Axis.

Epilepsy is a common chronic neurological disease that manifests as recurrent seizures. The incidence and prevalence of epilepsy in women are slightly lower than those in men. Polycystic ovary syndrome (PCOS), a reproductive endocrine system disease, is a complication that women with epilepsy are susceptible to, and its total prevalence is 8%-13% in the female population and sometimes as high as 26% in female epilepsy patients. The rate of PCOS increased markedly in female patients who chose valproate (VPA), to 1.95 times higher than that of other drugs. In addition, patients receiving other anti-seizure medications (ASMs), such as lamotrigine (LTG), oxcarbazepine (OXC), and carbamazepine (CBZ), also have reproductive endocrine abnormalities. Some scholars believe that the increase in incidence is related not only to epilepsy itself but also to ASMs. Epileptiform discharges can affect the activity of the pulse generator and then interfere with the reproductive endocrine system by breaking the balance of the hypothalamic-pituitary-ovarian (HPO) axis. ASMs may also cause PCOS-like disorders of the reproductive endocrine system through the HPO axis. Moreover, other factors such as hormone metabolism and related signalling pathways also play a role in it.