Intestinal epithelial dopamine receptor signaling drives sex-specific disease exacerbation in a mouse model of multiple sclerosis.

Although the gut microbiota can influence central nervous system (CNS) autoimmune diseases, the contribution of the intestinal epithelium to CNS autoimmunity is less clear. Here, we showed that intestinal epithelial dopamine D2 receptors (IEC DRD2) promoted sex-specific disease progression in an animal model of multiple sclerosis. Female mice lacking Drd2 selectively in intestinal epithelial cells showed a blunted inflammatory response in the CNS and reduced disease progression. In contrast, overexpression or activation of IEC DRD2 by phenylethylamine administration exacerbated disease severity. This was accompanied by altered lysozyme expression and gut microbiota composition, including reduced abundance of Lactobacillus species. Furthermore, treatment with N2-acetyl-L-lysine, a metabolite derived from Lactobacillus, suppressed microglial activation and neurodegeneration. Taken together, our study indicates that IEC DRD2 hyperactivity impacts gut microbial abundances and increases susceptibility to CNS autoimmune diseases in a female-biased manner, opening up future avenues for sex-specific interventions of CNS autoimmune diseases.

Anti-IgLON5 disease: a novel topic beyond neuroimmunology.

Anti-IgLON5 disease is a recently defined autoimmune disorder of the nervous system associated with autoantibodies against IgLON5. Given its broad clinical spectrum and extremely complex pathogenesis, as well as difficulties in its early diagnosis and treatment, anti-IgLON5 disease has become the subject of considerable research attention in the field of neuroimmunology. Anti-IgLON5 disease has characteristics of both autoimmunity and neurodegeneration due to the unique activity of the anti-IgLON5 antibody. Neuropathologic examination revealed the presence of a tauopathy preferentially affecting the hypothalamus and brainstem tegmentum, potentially broadening our understanding of tauopathies. In contrast to that seen with other autoimmune encephalitis-related antibodies, basic studies have demonstrated that IgLON5 antibody-induced neuronal damage and degeneration are irreversible, indicative of a potential link between autoimmunity and neurodegeneration in anti-IgLON5 disease. Herein, we comprehensively review and discuss basic and clinical studies relating to anti-IgLON5 disease to better understand this complicated disorder.

Repurposing carbamazepine for the treatment of amyotrophic lateral sclerosis in SOD1-G93A mouse model.

AIMS: To investigate the effect and mechanisms of carbamazepine (CBZ) on the onset and progression of amyotrophic lateral sclerosis (ALS) in SOD1-G93A mouse model. METHODS: Starting from 64 days of age, SOD1-G93A mice were orally administered with CBZ at 200 mg/kg once daily until death. The disease onset and life span of SOD1-G93A mice were recorded. Motor neurons (MNs) in anterior horn of spinal cord were quantified by Nissl staining and SMI-32 immunostaining. Hematoxylin and eosin (H&E), nicotinamide adenine dinucleotide hydrogen (NADH), modified Gomori trichrome (MGT), and α-bungarotoxin-ATTO-488 staining were also performed to evaluate muscle and neuromuscular junction (NMJ) damage. Expressions of aggregated SOD1 protein and autophagy-related proteins were further detected by Western blot and immunofluorescent staining. RESULTS: Carbamazepine treatment could delay the disease onset and extend life span of SOD1-G93A mice by about 14.5% and 13.9%, respectively. Furthermore, CBZ treatment reduced MNs loss by about 46.6% and ameliorated the altered muscle morphology and NMJ. Much more interestingly, mechanism study revealed that CBZ treatment activated autophagy via AMPK-ULK1 pathway and promoted the clearance of mutant SOD1 aggregation. CONCLUSION: Our findings uncovered the therapeutic effects of CBZ against disease pathogenesis in SOD1-G93A mice, indicating a promising clinical utilization of CBZ in ALS therapy.

n-butylidenephthalide treatment prolongs life span and attenuates motor neuron loss in SOD1G93A mouse model of amyotrophic lateral sclerosis.

AIMS: To evaluate the therapeutic effects of n-butylidenephthalide (BP) in SOD1G93A mouse model of amyotrophic lateral sclerosis and explore the possible mechanisms. METHODS: The SOD1G93A mice were treated by oral administration of BP (q.d., 400 mg/kg d) starting from 60 days of age and continuing until death. The rotarod test was performed to assess the disease onset. The expression levels of apoptosis-related proteins, inflammatory molecules, and autophagy-associated proteins were determined. The number of apoptotic motor neurons and the extent of microglial and astroglial activation were also assessed in the lumbar spinal cords of BP-treated mice. Grip strength test, hematoxylin-eosin staining, nicotinamide adenine dinucleotide hydrogen staining, and malondialdehyde assay were conducted to evaluate the muscle function and pathology. RESULTS: Although BP treatment did not delay the disease onset, it prolonged the life span and thereafter extended the disease duration in SOD1G93A mouse model of ALS. BP treatment also reduced the motor neuron loss through inhibiting apoptosis. We further demonstrated that the neuroprotective effects of BP might be resulted from the inhibition of inflammatory, oxidative stress, and autophagy. CONCLUSION: Our study suggests that BP may be a promising candidate for the treatment of ALS.