Cell-specific NFIA upregulation promotes epileptogenesis by TRPV4-mediated astrocyte reactivity.

BACKGROUND: The astrocytes in the central nervous system (CNS) exhibit morphological and functional diversity in brain region-specific pattern. Functional alterations of reactive astrocytes are commonly present in human temporal lobe epilepsy (TLE) cases, meanwhile the neuroinflammation mediated by reactive astrocytes may advance the development of hippocampal epilepsy in animal models. Nuclear factor I-A (NFIA) may regulate astrocyte diversity in the adult brain. However, whether NFIA endows the astrocytes with regional specificity to be involved in epileptogenesis remains elusive. METHODS: Here, we utilize an interference RNA targeting NFIA to explore the characteristics of NFIA expression and its role in astrocyte reactivity in a 4-aminopyridine (4-AP)-induced seizure model in vivo and in vitro. Combined with the employment of a HA-tagged plasmid overexpressing NFIA, we further investigate the precise mechanisms how NIFA facilitates epileptogenesis. RESULTS: 4-AP-induced NFIA upregulation in hippocampal region is astrocyte-specific, and primarily promotes detrimental actions of reactive astrocyte. In line with this phenomenon, both NFIA and vanilloid transient receptor potential 4 (TRPV4) are upregulated in hippocampal astrocytes in human samples from the TLE surgical patients and mouse samples with intraperitoneal 4-AP. NFIA directly regulates mouse astrocytic TRPV4 expression while the quantity and the functional activity of TRPV4 are required for 4-AP-induced astrocyte reactivity and release of proinflammatory cytokines in the charge of NFIA upregulation. NFIA deficiency efficiently inhibits 4-AP-induced TRPV4 upregulation, weakens astrocytic calcium activity and specific astrocyte reactivity, thereby mitigating aberrant neuronal discharges and neuronal damage, and suppressing epileptic seizure. CONCLUSIONS: Our results uncover the critical role of NFIA in astrocyte reactivity and illustrate how epileptogenic brain injury initiates cell-specific signaling pathway to dictate the astrocyte responses.

Distinct mechanisms underlying therapeutic potentials of CD20 in neurological and neuromuscular disease.

Cluster of differentiation 20 (CD20) is an integral membrane protein expressed mainly on different developmental stages of B lymphocytes and rarely on T lymphocytes, and it functions as a link to B cell antigen receptor (BCR) and immune microenvironment via regulating calcium ion influx, cell cycle progression and interaction between isotypic BCRs and their co-receptors. Diverse therapeutic monoclonal antibodies (mAbs) targeting CD20 are generated and grouped into two types based on the ability to redistribute CD20 into lipid rafts, which results in huge differences in response. Currently, multiple anti-CD20 mAbs have been approved as drugs for neurological and neuromuscular diseases with promising clinical efficacy. This review aims to summarize the potential mechanisms, development and current evidence for anti-CD20 therapy in neurological and neuromuscular diseases.

Inhibition of Transient Receptor Potential Vanilloid 4 (TRPV4) Mitigates Seizures.

Astrocytes are critical regulators of the immune/inflammatory response in several human central nervous system (CNS) diseases. Emerging evidence suggests that dysfunctional astrocytes are crucial players in seizures. The objective of this study was to investigate the role of transient receptor potential vanilloid 4 (TRPV4) in 4-aminopyridine (4-AP)-induced seizures and the underlying mechanism. We also provide evidence for the role of Yes-associated protein (YAP) in seizures. 4-AP was administered to mice or primary cultured astrocytes. YAP-specific small interfering RNA (siRNA) was administered to primary cultured astrocytes. Mouse brain tissue and surgical specimens from epileptic patient brains were examined, and the results showed that TRPV4 was upregulated, while astrocytes were activated and polarized to the A1 phenotype. The levels of glial fibrillary acidic protein (GFAP), cytokine production, YAP, signal transducer activator of transcription 3 (STAT3), intracellular Ca2+([Ca2+]i) and the third component of complement (C3) were increased in 4-AP-induced mice and astrocytes. Perturbations in the immune microenvironment in the brain were balanced by TRPV4 inhibition or the manipulation of [Ca2+]i in astrocytes. Knocking down YAP with siRNA significantly inhibited 4-AP-induced pathological changes in astrocytes. Our study demonstrated that astrocytic TRPV4 activation promoted neuroinflammation through the TRPV4/Ca2+/YAP/STAT3 signaling pathway in mice with seizures. Astrocyte TRPV4 inhibition attenuated neuroinflammation, reduced neuronal injury, and improved neurobehavioral function. Targeting astrocytic TRPV4 activation may provide a promising therapeutic approach for managing epilepsy.

A retrospective study of branch atheromatous disease: Analyses of risk factors and prognosis.

The theory of branch atheromatous disease (BAD) has been commonly underused in clinical practice and research since it was proposed in 1989. In this study, we sought to explore clinical characteristics of its substypes and biomarkers for prognosis of BAD. A total of 176 consecutive patients with BAD were classified into two groups: paramedianpontine artery group (PPA group, n=70) and lenticulostriate artery group (LSA group, n=106). Bivariate analyses were used to explore the relationship between white matter hyperintensities (WMHs), National Institutes of Health Stroke Scale (NIHSS) scores and prognosis evaluated by the modified Rank Scale (mRS) at 6th month after stroke. The differences in prevalence of diabetes mellitus and a history of ischemic heart disease were statistically significant between PPA group and LSA group (χ 2=8.255, P=0.004; χ 2=13.402, P<0.001). The bivariate analyses demonstrated a positive correlation between NIHSS and poor prognosis in patients with BAD and in the two subtype groups, and a positive correlation between WMHs and poor prognosis in the PPA group. It is concluded that a significantly higher prevalence of diabetes mellitus and a history of ischemic heart disease exist in the PPA group than in the LSA group. In addition, high grades of NIHSS scores imply poor prognosis in patients with BAD and in the two subtype groups. Moreover, WMHs are a positive predictor for poor prognosis in patients in the PPA group.

A Retrospective Study of Branch Atheromatous Disease: Analyses of Risk Factors and Prognosis / 华中科技大学学报（医学）（英德文版）

The theory of branch atheromatous disease (BAD) has been commonly underused in clinical practice and research since it was proposed in 1989.In this study,we sought to explore clinical characteristics of its substypes and biomarkers for prognosis of BAD.A total of 176 consecutive patients with BAD were classified into two groups:paramedianpontine artery group (PPA group,n=70) and lenticulostriate artery group (LSA group,n=106).Bivariate analyses were used to explore the relationship between white matter hyperintensities (WMHs),National Institutes of Health Stroke Scale (NIHSS) scores and prognosis evaluated by the modified Rank Scale (mRS) at 6th month after stroke.The differences in prevalence of diabetes mellitus and a history of ischemic heart disease were statistically significant between PPA group and LSA group (x2=8.255,P=0.004;x2=13.402,P＜0.001).The bivariate analyses demonstrated a positive correlation between NIHSS and poor prognosis in patents with BAD and in the two subtype groups,and a positive correlation between WMHs and poor prognosis in the PPA group.It is concluded that a significantly higher prevalence of diabetes mellitus and a history of ischemic heart disease exist in the PPA group than in the LSA group.In addition,high grades of NIHSS scores imply poor prognosis in patients with BAD and in the two subtype groups.Moreover,WMHs are a positive predictor for poor prognosis in patients in the PPA group.