IQGAP1 promotes chronic pain by regulating the trafficking and sensitization of TRPA1 channels.

TRPA1 channels have been implicated in mechanical and cold hypersensitivity in chronic pain. But how TRPA1 mediates this process is unclear. Here we show that IQ motif containing GTPase activating protein 1 is responsible using a combination of biochemical, molecular, Ca2+ imaging and behavioural approaches. TRPA1 and IQ motif containing GTPase activating protein 1 bind to each other and are highly colocalized in sensory dorsal root ganglia neurons in mice. The expression of IQ motif containing GTPase activating protein 1 but not TRPA1 is increased in chronic inflammatory and neuropathic pain. However, TRPA1 undergoes increased trafficking to the membrane of dorsal root ganglia neurons catalysed by the small GTPase Cdc42 associated with IQ motif containing GTPase activating protein 1, leading to functional sensitization of the channel. Activation of protein kinase A is also sufficient to evoke TRPA1 trafficking and sensitization. All these responses are, however, completely prevented in the absence of IQ motif containing GTPase activating protein 1. Concordantly, deletion of IQ motif containing GTPase activating protein 1 markedly reduces mechanical and cold hypersensitivity in chronic inflammatory and neuropathic pain in mice. IQ motif containing GTPase activating protein 1 thus promotes chronic pain by coupling the trafficking and signalling machineries to TRPA1 channels.

Neuronal growth and synaptogenesis are inhibited by prenatal methamphetamine exposure leading to memory impairment in adolescent and adult mice.

Synaptogenesis plays critical roles in learning and memory processes and is susceptible to substance abuse toxicity. The present study aimed to elucidate the long-lasting effects of prenatal methamphetamine exposure on synaptogenesis and learning and memory. The involvement of BDNF-TrkB signaling was also investigated. Pregnant mice (C57BL/6 JNc) were administered methamphetamine (5 mg/kg, s.c.) on gestation days 8-15. Primary hippocampal cultures were prepared from fetuses at gestational day 16.5 to study neuronal morphology and synaptogenesis. The expression of synaptic proteins, BDNF and TrkB receptor was determined in postnatal day 14 (PND14), adolescent and adult mice; memory tests were also conducted. MA exposure decreased axon length and diameter, and synaptic areas in the primary cultures. Presynaptic protein was decreased in the hippocampus of PND14 mice prenatally exposed to MA, while increases in postsynaptic protein (PSD-95) were found in MA-exposed adolescent and adult mice. BDNF expression was enhanced in the prefrontal cortex and striatum of MA-exposed PND14 mice. Memory impairment was observed in MA-exposed adolescent and adult mice compared to control mice. Prenatal MA exposure disrupted neuronal growth and synapse formation in the developing brain with only short-term interference of the BDNF-TrkB signaling pathway, resulting in the adaptation of postsynaptic neurons. Alterations in the developing brain and synaptogenesis lead to long-lasting learning and memory impairment.

Neuroprotective effect of a standardized extract of Centella asiatica ECa233 in rotenone-induced parkinsonism rats.

BACKGROUND: Mitochondrial dysfunction and reactive oxygen species (ROS) generation cause dopaminergic neurodegeneration in Parkinson's disease. The neuroprotective approach is a promising strategy to slow disease progression in Parkinson's disease. A standardized extract of Centella asiatica ECa233 has been previously reported to have pharmacological effects in the central nervous system. PURPOSE: This study aimed to determine the neuroprotective effect and mechanisms of ECa233 in rotenone-induced parkinsonism rats. METHODS: Rats were orally given either vehicle or ECa233 (10, 30 and 100 mg/kg) for 20 consecutive days. Rotenone (2.5 mg/kg i.p.) was given to parkinsonism (PD) and ECa-treated rats from day 15 to 20. Locomotor activity was recorded on day 1, 14, 17 and 20. Tyrosine-hydroxylase (TH) immunohistological staining was used to determine dopaminergic neurons in the substantia nigra and striatum. Furthermore, mitochondrial complex I activity, malondialdehyde (MDA) levels, superoxide dismutase (SOD) and catalase protein expression were measured in brain tissue. RESULTS: Rats receiving ECa233 30 mg/kg showed a significant increase in distances (p < 0.01) together with a higher number and intensity of dopaminergic neurons in the substantia nigra and striatum (p < 0.001) compared to PD rats. ECa233 (30 mg/kg) protected against mitochondrial complex I inhibition, decreased MDA levels (p < 0.05) and increased SOD (p < 0.01) and catalase (p < 0.05) expression. CONCLUSION: ECa233 can protect against rotenone-induced motor deficits and dopaminergic neuronal death. These effects are mediated through the protection of mitochondrial complex I activity, the effects of antioxidants and the enhancement of antioxidant enzyme expression.

Ginseng Extract G115 Attenuates Ethanol-Induced Depression in Mice by Increasing Brain BDNF Levels.

The decrease of brain-derived neurotrophic factor (BDNF) has been reported in alcohol use disorder and major depression. The effective treatment of these comorbid diseases remains undiscovered. Nutraceutical products are therefore proposed as an alternative approach to overcome this challenge. Ginseng extract G115, the standardized extract of Panax ginseng, is a widely-used nutraceutical that is beneficial for various central nervous system disorders. This study aimed to determine the antidepressant effect of ginseng extract G115 in ethanol-treated mice models. Mice received either water, amitriptyline, or various doses of G115 (p.o.) followed by water or ethanol (i.p.) for 8 days. The antidepressant activity was evaluated using forced swimming test. BDNF levels were measured from hippocampal and prefrontal cortex tissues. The results demonstrated that the increase of immobility time in depressant mice induced by ethanol was reversed by both G115 and amitriptyline treatment. A significant increase of BDNF levels in the hippocampus and prefrontal cortex was observed in ethanol-treated mice receiving G115. Taken together, this study provides scientific information on the use of G115 as an antidepressant that could be further used as a dietary supplement in comorbid alcohol use and major depressive disorders.