Objective: Minocycline, a tetracycline antibiotic, has shown anti-inflammatory effects in cerebral ischemia and neurodegenerative disease; however, the molecular mechanisms underlying this effect have not been clearly identified. Since NLRP3 inflammasome activation controls the maturation and release of proinflammatory cytokines, especially interleukin-1β (IL-1β) and IL-18 in ischemia stroke, we suppose that minocycline may be involved in the regulation of NLRP3 inflammasome activation. Methods: We investigated the effects of minocycline on NLRP3 inflammasome activation using the transient middle cerebral artery occlusion (tMCAO) mouse model and an in vitro oxygen-glucose deprivation/reoxygenation injury model in BV2 microglial cells. Results: We found that minocycline administrated 1 h after reperfusion can improve neurological disorder, reduce infarct volume, and alleviate cerebral edema. Meanwhile, we showed that minocycline prevented the activation of microglias and attenuated NLRP3 inflammasome signaling after tMCAO injury. Furthermore, we found that the pretreatment of minocycline significantly inhibited signal 1 and signal 2 of NLRP3 inflammasome activation in BV2 cells. Conclusion: We demonstrated that minocycline can ameliorate ischemia-induced brain damage via inhibiting NLRP3 inflammasome activation.

Itch is a common symptom in patients with skin and systemic diseases, but the effective treatment is limited. Here, we evaluated the anti-itch effects of the botulinum toxin type A (BoNT/A) using acute and chronic dry skin itch mouse models, which were induced by compound 48/80, chloroquine, and a mixture of acetone-diethylether-water treatment, respectively. Pretreatment of intradermal BoNT/A exerted long-term inhibitory effects on compound 48/80-induced and chloroquine-induced acute itch on days 1, 3, 7, and 14, but not on day 21, in mice. Furthermore, a single injection of BoNT/A reduced the expression of the transient receptor potential cation channel, subfamily V, member 1 (TRPV1), and the transient receptor potential cation channel, subfamily A, member 1 (TRPA1) at both transcriptional and translational levels in the dorsal root ganglia (DRG) in mice. Pretreatment of BoNT/A also attenuated chronic itch induced by acetone-diethylether-water treatment and abolished the upregulation of TRPA1 in the DRG. Thus, it was suggested that downregulation of the expression of TRPA1 and TRPV1 in the DRG may contribute toward the long-term anti-itch effects of a single injection of BoNT/A in mice and BoNT/A treatment may serve as an alternative strategy for anti-itch therapy.

Chronic stress is widely considered to trigger or enhance itch, especially for pruritic dermatitis. However, the molecular mechanisms linking chronic stress and itch are still unknown. The present study aimed to elucidate the role of adrenergic signaling in itch hypersensitivity following heterotypic chronic intermittent stress (HIS) in rats. HIS significantly increased hindlimb scratching, but not forepaw swiping, induced by intradermal injection of 5-hydroxytryptamine (5-HT) in the rat cheek. Coadministration of stress mediators such as norepinephrine or epinephrine dose-dependently increased both 5-HT-induced hindlimb scratching and 5-HT-induced forepaw swiping. HIS-induced itch hypersensitivity was attenuated by blockade of sympathetic signaling through guanethidine treatment, and systemic administration of the β-adrenoceptor antagonist propranolol and the β2-adrenoceptor antagonist butoxamine, but not on treatment with an α-adrenoceptor antagonist phentolamine and a β1-adrenoceptor antagonist atenolol. Moreover, HIS selectively increased the expression of β2-adrenoceptors and proinflammatory factors [tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and nerve growth factor (NGF)] in rat skin. The β-blockers propranolol and butoxamine abolished the upregulation of proinflammatory factors. The β2-adrenoceptor agonist terbutaline was sufficient to enhance the skin expression of TNF-α and IL-1β and to increase 5-HT-induced scratching in naive rats. Pretreatment with TNF-α could increase 5-HT-induced scratching. Together, these results demonstrate that β2-adrenoceptors mediate itch hypersensitivity following chronic stress by inducing proinflammatory factors, such as TNF-α, in the skin.

Background L-DOPA is still the gold-standard drug for the treatment of Parkinson's disease (PD). However, the long-term therapy often causes L-DOPA-induced dyskinesia (LID). Metabotropic glutamate receptor type 5 (mGluR5) is abundant in the basal ganglia, and its antagonists is thought to alleviates LID, but the underlying mechanisms have remained unclear. Methods We used 6-hydroxydopamine-lesioned rats to create PD rat model, PD rats were daily treated with L-DOPA alone or with MPEP 30 min before L-DOPA for 3 weeks, and at least 21 days of L-DOPA was administrated followed with microinjection of saline, CaMKII antagonist KN-93, anti-CREB, or anti-BDNF into the lesioned striatum of all the PD rats. The behavioral evaluation of abnormal involuntary movements(AIM) and rotational behavior tests were performed on the 2, 9, 11, 18, 21 and 23 days after drug application, and to tested the protein level of mGluR5, CaMKII, CREB and BDNF by western blot. Results Our results showed that MPEP cotreatment attenuates the abnormal involuntary movements, reversed the reduction of rotational response duration, and reduced overexpression of striatal mGluR5 and CaMKII/CREB/BDNF in the LID rats. Furthermore, we found that the CaMKII inhibitor KN-93, anti-CREB and anti-BDNF intrastriatal injection partly attenuates LID; KN-93 downregulated the striatal p-CaMKII, p-CREB and BDNF expression of the lesioned side, but the striatal mGluR5 expression without inhibition; anti-CREB downregulated the striatal p-CREB and BDNF expression of the lesioned side, but the striatal mGluR5 and p-CaMKII expression without inhibition; anti-BDNF downregulated the striatal BDNF expression of the lesioned side, but the mGluR5, CaMKII and CREB protein without inhibition. Conclusions These fundings suggested that mGluR5 specific antagonist MPEP attenuates L-DOPA-induced dyskinesia through affects CaMKII/CREB/BDNF molecular pathways in the striatum in this LID rat model.

Our previous studies demonstrated that effects of moxibustion heavily relied on heat-sensitization response, a specific sensation induced by moxibustion in the ill body. On the sensation, long-term potentiation (LTP) of prelimbic cortex was attributed to heat-sensitization responses. The N-methyl-D-aspartic acid (NMDA) receptor plays a key role in LTP induction; however, little is known about the role of NMDA receptor in heat-sensitization response. The present study investigated the role of NMDA receptor in heat-sensitization response, specifically, NMDA receptor was inhibited by competitive glutamatergic antagonist, (±)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), observing the frequency of heat-sensitization response in moxibustion treatment and evaluating the conducive outcomes to cerebral infarct rats for rehabilitation. Heat-sensitization response in cerebral infarct rats was regularly measured for all the samples when exposed to moxibustion. Intraperitoneal injection of CPP was conducted, and soon afterwards, a significant drop of heat-sensitization response in all the samples was measured. Moreover, moxibustion efficiency on rehabilitation was unfavourably affected in cerebral infarct rats when compared to vehicle injection control. This indicated that NMDA receptor antagonist made a negative impact on induction of heat-sensitization response and consequently affected cerebral infarct rats to rehabilitate under moxibustion treatment. It also suggested that activating NMDA receptor played a positive part in ischemic stroke rehabilitation, and regulating its activity could be a feasible way to increase heat-sensitization response, improving the effect of moxibustion.