Multiple functional therapeutic effects of DL-3-n-butylphthalide in the cuprizone model of demyelination.

AIMS: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). The disease mechanisms driving progressive MS remain unresolved. Without this information, current therapeutic strategies are unsatisfactory in preventing disease progression. Our previous work revealed that DL-3-n-butylphthalide (NBP) treatment reduced demyelination in an ethidium bromide mouse model of demyelination. Here, we examine the effect of NBP in the cuprizone model of demyelination by evaluating the pathologic, functional, and behavioral consequences of treatment with NBP. MATERIALS AND METHODS: Forty mice were divided randomly into 4 groups: a normal diet group, a cuprizone diet group, and two NBP groups (10 and 20 mg/kg). CNS infiltration by microglia, axon health and myelination were assessed using immunohistochemistry and electron microscopy, and the levels of cytoplasmic complexes were assessed by Western blotting. KEY FINDINGS: The results showed the neuroprotective effects of the NBP included suppressing the microglia activation through inhibition of nuclear factor-κB (NF-κB) expression, thus decreasing activation of the NF-κB signaling pathway. In particular, myelin density was increased due to an increased mean number of mature oligodendrocytes (OLs) in the high-dose NBP (20 mg/kg) subgroup through reduced oligodendrocyte apoptosis. Meanwhile, increased expression of myelin sheath proteins, including proteolipid protein (PLP) and myelin basic protein (MBP), was observed in the same subgroup. SIGNIFICANCE: These data suggest that NBP may not only have anti-inflammatory properties but also promote the survival of OLs in a mouse cuprizone model of demyelination. NBP may have a potential role in the treatment of MS.

Inhibition of ferroptosis processes ameliorates cognitive impairment in kainic acid-induced temporal lobe epilepsy in rats.

Hippocampal neuronal death plays a causal role in the cognitive impairment of temporal lobe epilepsy (TLE). Ferroptosis, a novel form of regulated cell death, is strongly linked to cognitive impairment. However, whether ferroptosis is associated with cognitive comorbidities of TLE is unknown. In this study, it was demonstrated that ferroptosis occurs in the hippocampus following kainic acid (KA)-induced TLE in rats. Treatment with ferrostatin-1, a specific inhibitor of ferroptosis, prevented the initiation and progression of ferroptosis in the hippocampus of KA-treated rats. This was through decreased expression of glutathione peroxidase 4, glutathione (GSH) depletion as well as lipid peroxides and iron accumulation. It was also found that ferrostatin-1 prevented hippocampal neuronal loss and rescued cognitive function in KA-induced TLE in rats. These results suggest that ferroptosis is involved in the cognitive impairment of KA-induced TLE in rats, and inhibition of ferroptosis processes ameliorates cognitive impairment in KA-induced TLE in rats.

Characteristics of Seizure and Antiepileptic Drug Utilization in Outpatients With Autoimmune Encephalitis.

Autoimmune encephalitis (AE) is one kind of encephalitis that associates with specific neuronal antigens. Most patients with AE likely suffer from seizures, but data on the characteristics of seizure and antiepileptic drugs (AEDs) utilization in this patient group remains limited. This study aimed to report the clinical status of seizure and AEDs treatment of patients with AE, and to evaluate the relationship between AEDs discontinuation and seizure outcomes. Patients with acute neurological disorders and anti-N-methyl-D-aspartate receptor (NMDAR), γ-aminobutyric acid B receptor (GABABR), leucine-rich glioma inactivated 1, or contactin-associated protein-like 2 (CASPR2) antibodies were included. As patients withdrew from AEDs, they were divided into the early withdrawal (EW, AEDs used ≤3 months) and late withdrawal (LW, AEDs used >3 months) groups. Seizure remission was defined as having no seizures for at least 1 year after the last time when AEDs were administered. Seizure outcomes were assessed on the basis of remission rate. The factors affecting the outcomes were assessed through Spearman analysis. In total, we enrolled 75 patients (39 patients aged <16 years, male/female = 39/36) for follow-up, which included 67 patients with anti-NMDAR encephalitis, 4 patients with anti-GABABR encephalitis, 2 patients with anti-voltage-gated potassium channel encephalitis, and 2 patients with coexisting antibodies. Among the 34 enrolled patients with anti-NMDAR encephalitis who were withdrawn from AEDs, only 5.8% relapse was reported during the 1-year follow-up, with no significant difference in the percentage of relapse between the EW and LW groups (P = 0.313). Fifteen patients (an average age of 6.8, 14 patients with anti-NMDAR encephalitis and 1 patient with anti-CASPR2 encephalitis) presented seizure remission without any AEDs. Seventy five percent of patients with anti-GABABR antibodies developed refractory seizure. Other risk factors which contributed to refractory seizure and seizure relapse included status epilepticus (P = 0.004) and cortical abnormalities (P = 0.028). Given this retrospective data, patients with AE have a high rate of seizure remission, and the long-term use of AEDs may not be necessary to control the seizure. Moreover, seizures in young patients with anti-NMDAR encephalitis presents self-limited. Patients with anti-GABABR antibody, status epilepticus, and cortical abnormalities are more likely to develop refractory seizure or seizure relapse.

The role of microglia in multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Microglia are the resident innate immune cells in the CNS; they play an important role in the processes of demyelination and remyelination in MS. Microglia can function as antigen-presenting cells and phagocytes. In the past, microglia were considered to be the same cell type as macrophages, and researchers have different opinions about the role of microglia in MS. This review focuses on the original classification of microglia and their role in the pathogenesis of MS. Moreover, we present a hypothetical model for the role of microglia in the pathogenesis of MS based on recent findings.