Inhibition of endoplasmic reticulum stress alleviates secondary injury after traumatic brain injury

Apoptosis after traumatic brain injury has been shown to be a major factor influencing prognosis and outcome. Endoplasmic reticulum stress may be involved in mitochondrial mediated neuronal apoptosis. Therefore, endoplasmic reticulum stress has become an important mechanism of secondary injury after traumatic brain injury. In this study, a rat model of traumatic brain injury was established by lateral fluid percussion injury. Fluorescence assays were used to measure reactive oxygen species content in the cerebral cortex. Western blot assays were used to determine expression of endoplasmic reticulum stress-related proteins. Hematoxylin-eosin staining was used to detect pathological changes in the cerebral cortex. Transmission electron microscopy was used to measure ultrastructural changes in the endoplasmic reticulum and mitochondria. Our results showed activation of the endoplasmic reticulum stress-related unfolded protein response. Meanwhile, both the endoplasmic reticulum stress response and mitochondrial apoptotic pathway were activated at different stages post-traumatic brain injury. Furthermore, pretreatment with the endoplasmic reticulum stress inhibitor, salubrinal（1 mg/kg）, by intraperitoneal injection 30 minutes before injury significantly inhibited the endoplasmic reticulum stress response and reduced apoptosis. Moreover, salubrinal promoted recovery of mitochondrial function and inhibited activation of the mitochondrial apoptotic pathway post-traumatic brain injury. These results suggest that endoplasmic reticulum stress might be a key factor for secondary brain injury post-traumatic brain injury.

Polydatin prevents the induction of secondary brain injury after traumatic brain injury by protecting neuronal mitochondria

Polydatin is thought to protect mitochondria in different cell types in various diseases.Mitochondrial dysfunction is a major contributing factor in secondary brain injury resulting from traumatic brain injury.To investigate the protective effect of polydatin after traumatic brain injury,a rat brain injury model of lateral fluid percussion was established to mimic traumatic brain injury insults.Rat models were intraperitoneally injected with polydatin(30 mg/kg)or the SIRT1 activator SRT1720(20 mg/kg,as a positive control to polydatin).At 6 hours post-traumatic brain injury insults,western blot assay was used to detect the expression of SIRT1,endoplasmic reticulum stress related proteins and p38 phosphorylation in cerebral cortex on the injured side.Flow cytometry was used to analyze neuronal mitochondrial superoxide,mitochondrial membrane potential and mitochondrial permeability transition pore opened.Ultrastructural damage in neuronal mitochondria was measured by transmission electron microscopy.Our results showed that after treatment with polydatin,release of reactive oxygen species in neuronal mitochondria was markedly reduced;swelling of mitochondria was alleviated;mitochondrial membrane potential was maintained;mitochondrial permeability transition pore opened.Also endoplasmic reticulum stress related proteins were inhibited,including the activation of p-PERK,spliced XBP-1 and cleaved ATF6.SIRT1 expression and activity were increased;p38 phosphorylation and cleaved caspase-9/3 activation were inhibited.Neurological scores of treated rats were increased and the mortality was reduced compared with the rats only subjected to traumatic brain injury.These results indicated that polydatin protectrd rats from the consequences of traumatic brain injury and exerted a protective effect on neuronal mitochondria.The mechanisms may be linked to increased SIRT1 expression and activity,which inhibits the p38 phosphorylation-mediated mitochondrial apoptotic pathway.This study was approved by the Animal Care and Use Committee of the Southern Medical University,China(approval number:L2016113)on January 1,2016.

Efficacy and safety of modified medium-chain triglyceride ketogenic diet in patients with drug-resistant epilepsy

Background Medium-chain triglyceride ketogenic diet(MCTKD)is previously less commonly used in China.This study was aimed to assess the efficacy and safety of the modified MCTKD in the treatment of drug-resistant epilepsy in Chinese patients.Methods Patients with drug-resistant epilepsy were enrolled to receive treatment with modified MCTKD in Guangdong Sanjiu Brain Hospital during December 2020 and September 2022.The modified MCTKD contained fat that provided 50–70%of the total energy,as well as proteins and carbohydrates that provided 20–30%and 20%of energy,respectively.The fat component was composed of 20–30%medium-chain triglycerides(MCTs)and 30–40%long-chain triglycerides.The efficacy and safety of the diet were assessed at 1,3 and 6 months.Results A total of 123 patients aged 2.5 to 65 years,were included in this study.The response rates at 1,3 and 6 months were 49.6%,43.1%,and 30.9%,respectively.The seizure freedom rates at 1,3 and 6 months were 12.2%,10.6%,and 6.5%,respectively.The retention rates at 1,3 and 6 months were 98.4%,65.0%and 33.3%respectively.Side effects occurred in 21.14%of patients,which were predominantly gastrointestinal symptoms such as abdominal pain,diarrhea,vomiting,and constipation,and most of them resolved after dietary adjustments.A total of 82 patients(66.7%)discontinued the treatment with the reason of refusing to eat(8.1%),poor efficacy(35.0%),poor compliance(4.9%),and inability to follow-up(9.8%).Only 4 patients(3.3%)withdrew the diet due to side effects.Conclusions The modified MCTKD with MCTs providing 20–30%of energy has a good safety in patients with drug-resistant epilepsy,but its effectiveness needs to be enhanced.Further modifications of MCTKD with an optimal energy ratio are required to achieve a better efficacy and safety.

Bilateral asymmetric tonic seizure in insuloopercular epilepsy:an anatomo-electroclinical study

Background:Insulo-opercular seizures are highly heterogeneous in seizure semiology and electrical features.Bilateral asymmetric limb posturing,as a classical pattern of supplementary sensorimotor area(SMA)seizure,also occurs in insulo-opercular epilepsy.This study was aimed to study the anatomo-electro-clinical correlations in bilateral asymmetric tonic seizures(BATS),in order to advance the understanding of insulo-opercular epilepsy.Methods:Eight patients with insulo-opercular epilepsy as confirmed by stereoelectroencephalography(SEEG)and manifesting BATS as the major ictal motor sign,in Guangdong Sanjiu Brain Hospital Epilepsy Center from 2014 to 2018,were employed in this study.The BATS of the patients were evaluated,and the semiologic features and concomitant intracerebral EEG changes were quantified.Then the variables were examined with Cluster Analysis,and the semiologic features were correlated with anatomic localization using the Kendall correlation test.Results:Of the 8 patients,the most frequent initial motor sign was bilateral asymmetric tonic posturing(62.5%).Facial tonic-clonic sign also had a high prevalence in the evolution of seizures(87.5%).The results of Cluster Analysis showed that the semiologic features were subdivided into two main groups,one group comprising exclusively BATS and the other including signs of focal tonic seizure,aura,focal limb tonic-clonic seizure(TCS),facial TCS,hypermotor behavior,eye movement,autonomic changes and generalized TCS.The BATS was strongly associated with the posterior long gyrus(PLG)of insula(t=0.732)and parietal operculum(t=1.000);the hypermotor behaviors were associated with the anterior long gyrus(ALG)(t=0.770);and the autonomic changes were associated with the anterior limiting sulcus(ALS)(t=0.734)and middle short gyrus(MSG)(t=0.700).Conclusions:The seizure semiology of insulo-opercular epilepsy is characterized,in temporal order,by BATS,with or without simultaneous hypermotor behaviors,and frequently ends up with facial tonic-clonic signs,which is different from that of the SMA seizure.The early spread network involving the posterior insular lobe and parietal operculum may contribute to this pattern of manifestation.

Effects of apolipoprotein A polymorphism on plasma levels of lipids, progression of carotid atherosclerosis and response to statin therapy

Background Studies have shown that the apt （a） gene （LPA） rs3798220 polymorphism is associated with thelevels of lipids and the curative effect of statin therapy for carotid atherosclerosis （CAS）. Whether carriers ofan apt （a） variant benefit more from statin remains unclear. Methods One hundred and three patients with CAS were recruited from April 2012 to April 2013 in the Shunde First People＇s Hospital Affiliated to Southern Medical University in Foshan. All patients were administered atorvastatin 20 mg/d and were followed-up for 2 years, with the levels of plasma Lp （a）, total cholesterol （TC）, triglyceride （TG）, high density lipoprotein （HDL）, low density lipoprotein （LDL）. LPA rs3798220 genotypes of all patients were analyzed. Results Statin treatment significantly reduced the levels of IMT, TC, TG, LDL and increased the level of HDL, but statin treatment did not reduce the level ofLp （a）. According to the curative effect of statin therapy in patients with CAS, rs3798220 polymorphism had a certain influence on LDL and TC levels, but not on the improvement of the IMT, TG, HDL and Lp （a）. Conclusion Rs 3798220 polymorphism has a certain impact on the curative effects of statin, on LDL and TC levels.