Increased systolic and diastolic blood pressure were significantly and positively associated with death and disability among patients with acute hemorrhagic stroke, but not acute ischemic stroke, in Inner Mongolia, China.

Methamphetamine (METH) is an amphetamine-typed stimulant drug that is increasingly being abused worldwide. Previous studies have shown that METH toxicity is systemic, especially targeting dopaminergic neurons in the central nervous system (CNS). However, the role of neuroinflammation in METH neurotoxicity remains unclear. We hypothesized that Toll-like receptor 4 (TLR4) and Caspase-11 are involved in METH-induced astrocyte-related neuroinflammation. We tested our hypothesis by examining the changes of TLR4 and Caspase-11 protein expression in primary cultured C57BL/6 mouse astrocytes and in the midbrain and striatum of mice exposed to METH with western blot and double immunofluorescence labeling. We also determined the effects of blocking Caspase-11 expression with wedelolactone (a specific inhibitor of Caspase-11) or siRNA on METH-induced neuroinflammation in astrocytes. Furthermore, we determined the effects of blocking TLR4 expression with TAK-242 (a specific inhibitor of TLR4) or siRNA on METH-induced neuroinflammation in astrocytes. METH exposure increased Caspase-11 and TLR4 expression both in vitro and in vivo, with the effects in vitro being dose-dependent. Inhibition of Caspase-11 expression with either wedelolactone or siRNAs reduced the expression of inflammasome NLRP3 and pro-inflammatory cytokines. In addition, blocking TLR4 expression inhibited METH-induced activation of NF-κB and Caspase-11 in vitro and in vivo, suggesting that TLR4-Caspase-11 pathway is involved in METH-induced neuroinflammation. These results indicate that Caspase-11 and TLR4 play an important role in METH-induced neuroinflammation and may be potential gene targets for therapeutics in METH-caused neurotoxicity.

Methamphetamine (METH) is an extremely addictive stimulant drug that is widely used with high potential of abuse. Previous studies have shown that METH exposure damages the nervous system, especially dopaminergic neurons. However, the exact molecular mechanisms of METH-induced neurotoxicity remain unclear. We hypothesized that caspase-11 is involved in METH-induced neuronal apoptosis. We tested our hypothesis by examining the change of caspase-11 protein expression in dopaminergic neurons (PC12 and SH-SY5Y) and in the midbrain of rats exposed to METH with Western blotting. We also determined the effects of blocking caspase-11 expression with wedelolactone (a specific inhibitor of caspase-11) or siRNA on METH-induced apoptosis in PC12 cells and SH-SY5Y cells using Annexin V and TUNEL staining. Furthermore, we observed the protein expression changes of the apoptotic markers, cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase 1 (PARP), after silencing the caspase-11 expression in rat midbrain by injecting LV-shcasp11 lentivirus using a stereotaxic positioning system. Results showed that METH exposure increased caspase-11 expression both in vitro and in vivo, with the effects in vitro being dose- and time-dependent. Inhibition of caspase-11 expression with either wedelolactone or siRNAs reduced the number of METH-induced apoptotic cells. In addition, blocking caspase-11 expression inhibited METH-induced activation of caspase-3 and PARP in vitro and in vivo, suggesting that caspase-11/caspase-3 signal pathway is involved in METH-induced neurotoxicity. These results indicate that caspase-11 plays an essential role in METH-induced neuronal apoptosis and may be a potential gene target for therapeutics in METH-caused neurotoxicity.

Methamphetamine (METH), an extremely and widely abused illicit drug, can cause serious nervous system damage and social problems. Previous research has shown that METH use causes dopaminergic neuron apoptosis and astrocyte-related neuroinflammation. However, the relationship of astrocytes and neurons in METH-induced neurotoxicity remains unclear. We hypothesized that chemokine interleukin (IL) eight released by astrocytes and C-X-C motif chemokine receptor 1 (CXCR1) in neurons are involved in METH-induced neuronal apoptosis. We tested our hypothesis by examining the changes of CXCR1 in SH-SY5Y cells and in the brain of C57BL/6 mice exposed to METH by western blotting and immunolabeling. We also determined the effects of knocking down CXCR1 expression with small interfering ribonucleic acid (siRNA) on METH-exposed SH-SY5Y cells. Furthermore, we detected the expression levels of IL-8 and the nuclear factor-kappa B (NF-κB) pathway in U87MG cells and then co-cultured the two cell types to determine the role of CXCR1 and IL-8 in neuronal apoptosis. Our results indicated that METH exposure increased CXCR1 expression both in vitro and in vivo, with the effects obtained in vitro being dose-dependent. Silencing of CXCR1 expression with siRNAs reduced the expression of cleaved caspase-3, cleaved poly (ADP-ribose) polymerase (PARP), and other related proteins. In addition, IL-8 expression and release were increased in METH-exposed U87MG cells, which is regulated by NF-κB pathway. Neuronal apoptosis was attenuated by siCXCR1 after METH treatment in the co-cultured cells, which can be reversed after exposure to recombinant IL-8. These results demonstrate that CXCR1 plays an important role in neuronal apoptosis induced by METH and may be a potential target for METH-induced neurotoxicity therapy.Highlights Methamphetamine exposure upregulated the expression of CXCR1.Methamphetamine exposure increased the expression of interleukin-8 through nuclear factor-kappa B pathway.Activation of CXCR1 by interleukin-8 induces an increase in methamphetamine-related neuronal apoptosis.