Neuroprotective effect of histamine H3 receptor blockade on methamphetamine-induced cognitive impairment in mice.

OBJECTIVE: Methamphetamine (METH) exposure is commonly believed to result in cognitive impairment. Histamine H3 receptor (H3R) antagonists reportedly have potential applications for treating cognitive impairment accompanied by various neuropsychiatric disorders. The present study aimed to investigate the effect of H3R blockade by Thioperamide (THIO) on METH-induced cognitive impairment and the underlying mechanism. METHODS: In Experiment 1, C57BL/6 mice received daily injections of saline or 5 mg/kg METH for 5 consecutive days. The Novel Object Recognition (NOR) and Morris water maze (MWM) tasks were used to assess cognitive functions of mice. H3R protein expression and apoptosis were subsequently measured in the hippocampus. In Experiment 2, HT22 cells were first treated with ddH2O or 3 mM METH. The cell survival rate and H3R protein level were subsequently assessed. In Experiment 3, the animals were first treated with saline or 20 mg/kg THIO for 7 days, followed by co-administration of either saline or 5 mg/kg METH for an additional 5 days. The remaining experiments were carried out in the same manner as Experiment 1. In Experiment 4, HT22 cells were pretreated with either ddH2O or 5 mM THIO for 2 h, followed by ddH2O or 3 mM METH treatment for an additional 12 h. The remaining experiments were carried out in the same manner as Experiment 2. In Experiment 5, the changes in MEK1/2, p-MEK1/2, ERK1/2 and p-ERK1/2 protein levels were examined in the hippocampus of all mice from Experiment 3 and HT22 cells from Experiment 4. RESULTS: METH-treated mice showed significantly worsened NOR and MWM performance, along with markably hippocampal apoptosis. A significantly lower cell survival rate was observed in METH-treated HT22 cells. Increased levels of H3R protein were found in both METH-treated mice and HT22 cells. THIO significantly improved METH-induced cognitive impairment in mice and toxicity in HT22 cells. METH significantly increased the level of p-MEK1/2 and p-ERK1/2 proteins in the hippocampus of mice and HT22 cells, which was reversed by THIO pretreatment. CONCLUSION: Our findings reveal that H3R blockade by THIO yields a neuroprotective effect against METH-induced cognitive impairment in mice and toxicity in HT22 cells via the raf-MEK-ERK signaling pathway.

The Significance of NLRP Inflammasome in Neuropsychiatric Disorders.

The NLRP inflammasome is a multi-protein complex which mainly consists of the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain. Its activation is linked to microglial-mediated neuroinflammation and partial neuronal degeneration. Many neuropsychiatric illnesses have increased inflammatory responses as both a primary cause and a defining feature. The NLRP inflammasome inhibition delays the progression and alleviates the deteriorating effects of neuroinflammation on several neuropsychiatric disorders. Evidence on the central effects of the NLRP inflammasome potentially provides the scientific base of a promising drug target for the treatment of neuropsychiatric disorders. This review elucidates the classification, composition, and functions of the NLRP inflammasomes. It also explores the underlying mechanisms of NLRP inflammasome activation and its divergent role in neuropsychiatric disorders, including Alzheimer's disease, Huntington's disease, Parkinson's disease, depression, drug use disorders, and anxiety. Furthermore, we explore the treatment potential of the NLRP inflammasome inhibitors against these disorders.

The effect of the NLRP1 inflammasome on methamphetamine-induced cognitive impairment in rats.

Methamphetamine (METH) use disorder has been shown to be in high comorbidity with cognitive deficits. METH-induced cognitive deficits are accompanied by neurotoxicity which could result from neuroinflammation. The potential role of NLRP1 inflammasome (NLRP1) and the downstream signalling pathway in METH-induced cognitive impairment was explored in the current study. Cognitive functions and the changes of NLRP1/Caspase-1/GSDMD signalling pathway were firstly determined in rats receiving daily injections of METH. Subsequently, the effects of aspirin-triggered-lipoxin A4 (ATL), a potent anti-inflammatory mediator, and NLRP1 siRNA was investigated were investigated in both METH-treated rats and HT22 cells. METH induces significant cognitive deficits in rats, using the NOR test. METH-induced cognitive impairment was in line with increased activities of NLRP1, cleaved-Caspase-11, IL-1ß and TNF-α and the presence of GSDMD-mediated pyroptosis in the hippocampus of rats. NLRP1 inhibition by ATL significantly attenuated METH-induced cognitive impairment, in conjunction with the decreased activities of NLRP1 and cleaved-Caspase-1, IL-1ß and TNF-α. ATL and NLRP1 siRNA also prevented the presence of apoptosis in the hippocampus of METH-treated rats and the cell death in METH-treated HT22 cells. These results reveal a novel role of NLRP1 and the downstream signaling pathways in the complex actions of METH-induced cognitive deficits.

Inhibition of PLCß1 signaling pathway regulates methamphetamine self-administration and neurotoxicity in rats.

Studies have shown that the central renin-angiotensin system is involved in neurological disorders. Our previous studies have demonstrated that angiotensin II receptor type 1 (AT1R) in the brain could be a potential target against methamphetamine (METH) use disorder. The present study was designed to investigate the underlying mechanisms of the inhibitory effect of AT1R on various behavioural effects of METH. We first examined the effect of AT1R antagonist, candesartan cilexetil (CAN), on behavioural and neurotoxic effects of METH. Furthermore, we studied the role of phospholipase C beta 1 (PLCß1) blockade behavioural and neurotoxic effects of METH. The results showed that CAN significantly attenuated METH-induced behavioral disorders and neurotoxicity associated with increased oxidative stress. AT1R and PLCß1 were significantly upregulated in vivo and in vitro. Inhibition of PLCß1 effectively alleviated METH-induced neurotoxicity and METH self-administration (SA) by central blockade of the PLCß1 involved signalling pathway. PLCß1 blockade significantly decreased the reinforcing and motivation effects of METH. PLCß1 involved signalling pathway, as well as a more specific role of PLCß1, involved the inhibitory effects of CAN on METH-induced behavioural dysfunction and neurotoxicity. Collectively, our findings reveal a novel role of PLCß1 in METH-induced neurotoxicity and METH use disorder.