Journal of neurochemistry
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Journal of neurochemistry · Dec 2015
Acrolein contributes to TRPA1 up-regulation in peripheral and central sensory hypersensitivity following spinal cord injury.
Acrolein, an endogenous aldehyde, has been shown to be involved in sensory hypersensitivity after rat spinal cord injury (SCI), for which the pathogenesis is unclear. Acrolein can directly activate a pro-algesic transient receptor protein ankyrin 1 (TRPA1) channel that exists in sensory neurons. Both acrolein and TRPA1 mRNA are elevated post SCI, which contributes to the activation of TRPA1 by acrolein and consequently, neuropathic pain. ⋯ Finally, our data also further support the notion that acrolein scavenging may be an effective therapeutic approach to alleviate neuropathic pain after SCI. We propose that the trauma-mediated elevation of acrolein causes neuropathic pain through at least two mechanisms: acrolein stimulates the production of transient receptor protein ankyrin 1 (TRPA1) in both central and peripheral locations, and it activates TRPA1 channels directly. Therefore, acrolein appears to be a critical factor in the pathogenesis of post-SCI sensory hypersensitivity, becoming a novel therapeutic target to relieve both acute and chronic post-SCI neuropathic pain.
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Journal of neurochemistry · Dec 2015
Liraglutide is neurotrophic and neuroprotective in neuronal cultures and mitigates mild traumatic brain injury in mice.
Traumatic brain injury (TBI), a brain dysfunction for which there is no present effective treatment, is often caused by a concussive impact to the head and affects an estimated 1.7 million Americans annually. Our laboratory previously demonstrated that exendin-4, a long-lasting glucagon-like peptide 1 receptor (GLP-1R) agonist, has neuroprotective effects in cellular and animal models of TBI. Here, we demonstrate neurotrophic and neuroprotective effects of a different GLP-1R agonist, liraglutide, in neuronal cultures and a mouse model of mild TBI (mTBI). ⋯ Liraglutide produced neurotrophic and neuroprotective effects similar to those of exendin-4 in vitro, likely involving the cAMP/PKA/pCREB pathway. Our findings in cell culture were well-translated in a weight-drop mTBI mouse model. Post-treatment with a clinically relevant dose of liraglutide for 7 days in mice ameliorated memory impairments caused by mTBI.
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Journal of neurochemistry · Dec 2015
Deficits in behavioral sensitization and dopaminergic responses to methamphetamine in adenylyl cyclase 1/8-deficient mice.
The cAMP/protein kinase A pathway regulates methamphetamine (METH)-induced neuroplasticity underlying behavioral sensitization. We hypothesize that adenylyl cyclases (AC) 1/8 mediate these neuroplastic events and associated striatal dopamine regulation. Locomotor responses to METH (1 and 5 mg/kg) and striatal dopamine function were evaluated in mice lacking AC 1/8 (DKO) and wild-type (WT) mice. ⋯ AC 1/8 double knockout (DKO) mice showed heightened basal locomotor activity and dorsal striatal dopamine responsivity. Conversely, methamphetamine-induced locomotor activity was attenuated in DKO mice, accompanied by reductions in dopamine and HVA content and impaired DARPP-32 activation. These findings indicate AC 1/8 signaling regulates the sensitivity of the nigrostriatal pathway subserving stimulant and neuroadaptive sensitizing effects of methamphetamine. 3-MT, 3-methoxytyramine; Ca(2+), calcium; CaM, calmodulin; cdk5; cyclin-dependent kinase 5; DA, dopamine; DARPP-32, dopamine- and cAMP-regulated phosphoprotein; D1R, dopamine D1 receptor; HVA, homovanillic acid; PKA, protein kinase A.
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Journal of neurochemistry · Nov 2015
Soluble amyloid precursor protein alpha inhibits tau phosphorylation through modulation of GSK3β signaling pathway.
We recently found that sAPPα decreases amyloid-beta generation by directly associating with β-site amyloid precursor protein (APP)-converting enzyme 1 (BACE1), thereby modulating APP processing. Because inhibition of BACE1 decreases glycogen synthase kinase 3 beta (GSK3β)-mediated Alzheimer's disease (AD)-like tau phosphorylation in AD patient-derived neurons, we determined whether sAPPα also reduces GSK3β-mediated tau phosphorylation. We initially found increased levels of inhibitory phosphorylation of GSK3β (Ser9) in primary neurons from sAPPα over-expressing mice. ⋯ Importantly, the reductions in GSK3β activity and tau phosphorylation elicited by sAPPα were prevented by BACE1 but not γ-secretase inhibition. In accord, AD mice over-expressing human sAPPα had less GSK3β activity and tau phosphorylation compared with controls. These results implicate a direct relationship between APP β-processing and GSK3β-mediated tau phosphorylation and further define the central role of sAPPα in APP autoregulation and AD pathogenesis.
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Journal of neurochemistry · Nov 2015
Editorial CommentAn integrated energy plan for activated neurons.
This Editorial highlights an ingenious study by Li and Freeman published in this issue of J. Neurochem. ⋯ To that end, the authors have designed a new approach that consists to record at the same time (100 ms resolution) extracellular glucose and lactate concentrations using electrochemical sensing microelectrodes equally distant from a microelectrode that registers the multicellular activity in response to light-dependent stimuli (contrast levels from 10% to 80%). While this approach does, however, not evaluate the metabolic coupling between astrocytes and neurons, it proposes a new design which combined with molecular strategies specifically toward the glial or neuronal compartments will certainly help to demonstrate new distinctive features of this interesting question.