Adjudin protects blood-brain barrier integrity and attenuates neuroinflammation following intracerebral hemorrhage in mice.

Secondary brain injury exacerbates neurological dysfunction and neural cell death following intracerebral hemorrhage (ICH), targeting the pathophysiological mechanism of the secondary brain injury holds promise for improving ICH outcomes. Adjudin, a potential male contraceptive, exhibits neuroprotective effects in brain injury disease models, yet its impact in the ICH model remains unknown. In this study, we investigated the effects of adjudin on brain injury in a mouse ICH model and explored its underlying mechanisms. ICH was induced in male C57BL/6 mice by injecting collagenase into the right striatum. Mice received adjudin treatment (50 mg/kg/day) for 3 days before euthanization and the perihematomal tissues were collected for further analysis. Adjudin significantly reduced hematoma volume and improved neurological function compared with the vehicle group. Western blot showed that Adjudin markedly decreased the expression of MMP-9 and increased the expression of tight junctions (TJs) proteins, Occludin and ZO-1, and adherens junctions (AJs) protein VE-cadherin. Adjudin also decreased the blood-brain barrier (BBB) permeability, as indicated by the reduced albumin and Evans Blue leakage, along with a decrease in brain water content. Immunofluorescence staining revealed that adjudin noticeably reduced the infiltration of neutrophil, activation of microglia/macrophages, and reactive astrogliosis, accompanied by an increase in CD206 positive microglia/macrophages which exhibit phagocytic characteristics. Adjudin concurrently decreased the generation of proinflammatory cytokines, such as TNF-α and IL-1ß. Additionally, adjudin increased the expression of aquaporin 4 (AQP4). Furthermore, adjudin reduced brain cell apoptosis, as evidenced by increased expression of anti-apoptotic protein Bcl-2, and decreased expression of apoptosis related proteins Bax, cleaved caspase-3 and fewer TUNEL positive cells. Our data suggest that adjudin protects against ICH-induced secondary brain injury and may serve as a potential neuroprotective agent for ICH treatment.

Ion Channel Dysregulation Following Intracerebral Hemorrhage.

Injury to the brain after intracerebral hemorrhage (ICH) results from numerous complex cellular mechanisms. At present, effective therapy for ICH is limited and a better understanding of the mechanisms of brain injury is necessary to improve prognosis. There is increasing evidence that ion channel dysregulation occurs at multiple stages in primary and secondary brain injury following ICH. Ion channels such as TWIK-related K+ channel 1, sulfonylurea 1 transient receptor potential melastatin 4 and glutamate-gated channels affect ion homeostasis in ICH. They in turn participate in the formation of brain edema, disruption of the blood-brain barrier, and the generation of neurotoxicity. In this review, we summarize the interaction between ions and ion channels, the effects of ion channel dysregulation, and we discuss some therapeutics based on ion-channel modulation following ICH.

Botulinum toxin type A reduces the expression of transient receptor potential melastatin 3 and transient receptor potential vanilloid type 4 in the trigeminal subnucleus caudalis of a rat model of trigeminal neuralgia.

This study was designed to investigate the expression of transient receptor potential melastatin 3 (TRPM3) and transient receptor potential vanilloid type 4 (TRPV4) in the trigeminal spinal subnucleus caudalis of a rat model of trigeminal neuralgia (TN). The influence of botulinum toxin type A (BTX-A) on the expression of these channels was also explored. In this study, a model was established involving chronic constriction injury to the infraorbital nerve (ION-CCI), inducing TN. To explore the effects of BTX-A and whether it was dose related, rats were divided randomly into four groups: a control group, an ION-CCI group, a 3 U group, and a 10 U group (which received 3 and 10 U/kg BTX-A injections, respectively). Von Frey hairs were used to determine the pain threshold of the rats. The expression of TRPM3 and TRPV4 in the trigeminal spinal subnucleus caudalis was detected using western blots and immunohistochemistry. The pain thresholds of rats decreased to a minimum 14 days after ION-CCI. Compared with the ION-CCI group, the pain thresholds of the 3 and 10 U groups were significantly higher 4 days after the subcutaneous injection of BTX-A (P<0.05). The expression of TRPM3 and TRPV4 in the ION-CCI group was significantly higher than that in the control group (P<0.05). TRPM3 and TRPV4 expression in the 3 and 10 U groups was significantly lower than that in the ION-CCI group (P<0.05). In conclusion, overexpression of TRPM3 and TRPV4 can jointly mediate the occurrence of mechanical hyperalgesia in TN. The analgesic effects of BTX-A may be related to the inhibition of TRPM3 and TRPV4 expression.