Parvalbumin Regulates GAD Expression through Calcium Ion Concentration to Affect the Balance of Glu-GABA and Improve KA-Induced Status Epilepticus in PV-Cre Transgenic Mice.

Aims: the study aimed to (i) use adeno-associated virus technology to modulate parvalbumin (PV) gene expression, both through overexpression and silencing, within the hippocampus of male mice and (ii) assess the impact of PV on the metabolic pathway of glutamate and γ-aminobutyric acid (GABA). Methods: a status epilepticus (SE) mouse model was established by injecting kainic acid into the hippocampus of transgenic mice. When the seizures of mice reached SE, the mice were killed at that time point and 30 min after the onset of SE. Hippocampal tissues were extracted and the mRNA and protein levels of PV and the 65 kDa (GAD65) and 67 kDa (GAD67) isoforms of glutamate decarboxylase were assessed using real-time quantitative polymerase chain reaction and Western blot, respectively. The concentrations of glutamate and GABA were detected with high-performance liquid chromatography (HPLC), and the intracellular calcium concentration was detected using flow cytometry. Results: we demonstrate that the expression of PV is associated with GAD65 and GAD67 and that PV regulates the levels of GAD65 and GAD67. PV was correlated with calcium concentration and GAD expression. Interestingly, PV overexpression resulted in a reduction in calcium ion concentration, upregulation of GAD65 and GAD67, elevation of GABA concentration, reduction in glutamate concentration, and an extension of seizure latency. Conversely, PV silencing induced the opposite effects. Conclusion: parvalbumin may affect the expression of GAD65 and GAD67 by regulating calcium ion concentration, thereby affecting the metabolic pathways associated with glutamate and GABA. In turn, this contributes to the regulation of seizure activity.

Astragalus polysaccharides ameliorate epileptogenesis, cognitive impairment, and neuroinflammation in a pentylenetetrazole-induced kindling mouse model.

Background: Epilepsy is a prevalent neurological disease where neuroinflammation plays a significant role in epileptogenesis. Recent studies have suggested that Astragalus polysaccharides (APS) have anti-inflammatory properties, which make them a potential candidate for neuroprotection against central nervous system disease. Nevertheless, the extent of their effectiveness in treating epilepsy remains enigmatic. Therefore, our study aims to investigate the potential of APS to mitigate epileptogenesis and its comorbidities by exploring its underlying mechanism. Methods: Initially, we employed pentylenetetrazol-induced seizure mice to validate APS' effectiveness. Subsequently, we employed network pharmacology analysis to probe the possible targets and signaling pathways of APS in treating epilepsy. Ultimately, we verified the key targets and signaling pathways experimentally, predicting their mechanisms of action. Results: APS have been observed to disturb the acquisition process of kindling, leading to reduced seizure scores and a lower incidence of complete kindling. Moreover, APS has been found to improve cognitive impairments and prevent hippocampal neuronal damage during the pentylenetetrazole (PTZ)-kindling process. Subsequent network pharmacology analysis revealed that APS potentially exerted their anti-epileptic effects by targeting cytokine and toll-like receptor 4/nuclear factor kappa B (TLR4/NF-κB) signaling pathways. Finally, experimental findings showed that APS efficiently inhibited the activation of astrocytes and reduced the release of pro-inflammatory mediators, such as interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). In addition, APS impeded the activation of the TLR4/NF-κB signaling cascade in a PTZ-induced kindling mouse model. Conclusion: The outcomes of our study suggest that APS exerts an impact on epileptogenesis and mitigates cognitive impairment by impeding neuroinflammatory processes. The mechanism underlying these observations may be attributed to the modulation of the TLR4/NF-κB signaling pathway, resulting in a reduction of the release of inflammatory mediators. These findings partially agree with the predictions derived from network pharmacology analyses. As such, APS represents a potentially innovative and encouraging adjunct therapeutic option for epileptogenesis and cognitive deficit.

Modified Magnetic Resonance Imaging Burden of Cerebral Small Vessel Disease and Related Risk Factors in Patients With Thalassemia.

OBJECTIVE: This study aimed to explore the burden of magnetic resonance imaging (MRI) of cerebral small vessel disease (CSVD) in patients with thalassemia and related risk factors. METHODS: The clinical data and MRI of patients with thalassemia were retrospectively analyzed, and non-thalassemia controls with matched sex and age were selected. The modified MRI burden of CSVD included recent small subcortical infarct, presumed vasogenic white matter hyperintensity, presumed vasogenic lacunae, perivascular space (PVS), and brain atrophy. RESULTS: This study included 110 patients in each of the thalassemia and control groups. There was no significant difference in sex, age, and common cerebrovascular disease risk factors between the 2 groups. The patients with thalassemia had a higher red blood cell count and lower content of hemoglobin. The PVS and modified MRI burden scores in the thalassemia group were higher than in the control group. With the increase in age, patients with thalassemia have a more severe CSVD burden. CONCLUSION: Patients with thalassemia have a heavier modified MRI burden of CSVD than non-thalassemia patients, particularly PVS, and aging is an important risk factor for CSVD changes.

White matter abnormalities and multivariate pattern analysis in anti-NMDA receptor encephalitis.

Objective: This study aimed to investigate white matter (WM) microstructural alterations and their relationship correlation with disease severity in anti-NMDA receptor (NMDAR) encephalitis. Multivariate pattern analysis (MVPA) was applied to discriminate between patients and healthy controls and explore potential imaging biomarkers. Methods: Thirty-two patients with anti-NMDAR encephalitis and 26 matched healthy controls underwent diffusion tensor imaging. Tract-based spatial statistics and atlas-based analysis were used to determine WM microstructural alterations between the two groups. MVPA, based on a machine-learning algorithm, was applied to classify patients and healthy controls. Results: Patients exhibited significantly reduced fractional anisotropy in the corpus callosum, fornix, cingulum, anterior limb of the internal capsule, and corona radiata. Moreover, mean diffusivity was increased in the anterior corona radiata and body of the corpus callosum. On the other hand, radial diffusivity was increased in the anterior limb of the internal capsule, cingulum, corpus callosum, corona radiata, and fornix. WM changes in the cingulum, fornix, and retrolenticular part of the internal capsule were correlated with disease severity. The accuracy, sensitivity, and specificity of fractional anisotropy-based classification were each 78.33%, while they were 67.71, 65.83, and 70% for radial diffusivity. Conclusion: Widespread WM lesions were detected in anti-NMDAR encephalitis. The correlation between WM abnormalities and disease severity suggests that these alterations may serve a key role in the pathophysiological mechanisms of anti-NMDAR encephalitis. The combination of tract-based spatial statistics and MVPA may provide more specific and complementary information at the group and individual levels.