Neuropharmacology
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Aberrant CDK5 activity is implicated in a number of neurodegenerative disorders. Isoflurane exposure leads to neuronal apoptosis, and subsequent learning and memory defects in the developing brain. The present study was designed to examine whether and how CDK5 activity plays a role in developmental isoflurane neurotoxicity. ⋯ Moreover, Roscovitine remarkably alleviated the learning and memory deficits induced by postnatal isoflurane exposure. These results indicated that aberrant CDK5 activity-dependent MEF2 phosphorylation mediates developmental isoflurane neurotoxicity. Inhibition of CDK5 overactivation contributes to the relief of isoflurane neurotoxicity in the developing brain.
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Astrocytic glutamate transporter 1 (GLT-1) is responsible for the majority of extracellular glutamate clearance and is essential for preventing excitotoxicity in the brain. Up-regulation of GLT-1 shows benefit effect on ischemia-induced neuronal damage. In present study, we examined the effect of histamine, a neurotransmitter or neuromodulator, on GLT-1 expression and function. ⋯ In addition, histidine, the precursor of histamine, also showed neuroprotection against ischemic injury, which was accompanied by reversion of declined expression of GLT-1 in adult rats subjected to middle cerebral artery occlusion (MCAO). These neuroprotective effects of histamine/histidine were blocked by GLT-1 specific inhibitor dihydrokainate or H1 receptor antagonist. In summary, our results suggest that histamine up-regulates GLT-1 expression and function via astrocytic H1 receptors, thus resulting in neuroprotection against excitotoxicity and ischemic injury.
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The two most studied endocannabinoids are anandamide (AEA), principally catalyzed by fatty-acid amide hydrolase (FAAH), and 2-arachidonoyl glycerol (2-AG), mainly hydrolyzed by monoacylglycerol lipase (MGL). Inhibitors targeting these two enzymes have been described, including URB597 and URB602, respectively. Several recent studies examining the contribution of CB₁ and/or CB₂ receptors on the peripheral antinociceptive effects of AEA, 2-AG, URB597 and URB602 in neuropathic pain conditions using either pharmacological tools or transgenic mice separately have been reported, but the exact mechanism is still uncertain. ⋯ Furthermore, the antinociceptive effects for AEA and URB597 were observed in cnr2KO mice but absent in cnr1KO mice, whereas the effects of 2-AG, WIN and URB602 were altered in both of these transgenic mice. Complementary genetic and pharmacological approaches revealed that the anti-hyperalgesic effects of 2-AG and URB602 required both CB₁ and CB₂ receptors, but only CB₂ receptors mediated its anti-allodynic actions. The antinociceptive properties of AEA and URB597 were mediated only by CB₁ receptors.
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Dopamine (DA) replacement therapy with l-DOPA is the standard treatment for Parkinson's disease (PD). Unfortunately chronic treatment often leads to the development of abnormal involuntary movements (AIMs) referred to as L-DOPA-induced dyskinesia (LID). Accumulating evidence has shown that compensatory plasticity in serotonin (5-HT) neurons contributes to LID and recent work has indicated that acute 5-HT transporter (SERT) blockade provides anti-dyskinetic protection. ⋯ Neurochemical analysis of striatal tissue indicated that a 3 week SERT blockade increased DA levels in L-DOPA-treated rats. Pharmacologically, anti-dyskinetic effects were partially reversed with WAY100635 signifying involvement of the 5-HT1A receptor. Collectively, these findings demonstrate that prolonged SERT inhibition provides enduring anti-dyskinetic effects in part via 5-HT(1A) receptors while maintaining L-DOPA's anti-parkinsonian efficacy by enhancing striatal DA levels.
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mGlu7 receptors are coupled to Gi/Go-proteins and activate multiple transduction pathways, including inhibition of adenylyl cyclase activity and stimulation of ERK1/2 and JNK pathways. mGlu7 receptors play an important role in cognition and emotion and are involved in stress-related disorders such as anxiety and depression and in susceptibility to convulsive seizures. In spite of these potential clinical implications, little is known on the mechanisms that regulate mGlu7-receptor signaling. Here we show that mGlu7 receptor-dependent signaling pathways were regulated in a complementary manner by different GRK subtypes, with GRK4 affecting the adenylyl cyclase and the JNK pathways, and GRK2 selectively affecting the ERK1/2 pathway. ⋯ Finally we found that β-arrestin1 amplified mGlu7 receptor-dependent ERK1/2 activation in response to L-AP4 (an orthosteric agonist), but not in response to AMN082 (an atypical mGlu7-receptor allosteric agonist). The different effect of β-arrestin1 on L-AP4- and AMN082-stimulated ERK1/2 phosphorylation is in line with the emerging concept of β-arrestin-biased agonists. The present study may open new perspectives in elucidating the physio-pathological roles of the mGlu7 receptor and may provide new insights for the possibility to develop specific (biased) agonists that can selectively activate different signaling pathways.