Neuropharmacology
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Recently, increasing evidence has shown that cell cycle activation is a key factor of neuronal death and neurological dysfunction after traumatic brain injury (TBI). This study aims to investigate the effects of Honokiol, a cell cycle inhibitor, on attenuating the neuronal damage and facilitating functional recovery after TBI in rats, in an attempt to unveil its underlying molecular mechanisms in TBI. This study suggested that delayed intravenous administration of Honokiol could effectively ameliorate TBI-induced sensorimotor and cognitive dysfunctions. ⋯ Furthermore, the expression of some of the key cell cycle proteins such as cyclin D1 and E2F1 and the associated apoptosis in neurons were both remarkably attenuated by Honokiol treatment. These results show that delayed intravenous administration of Honokiol could effectively improve the functional recovery and attenuate the neuronal cell death, which is probably, at least in part, attributed to its role as a cell cycle inhibitior. This might give clues to developing attractive therapies for future clinical trials.
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Impaired insulin signaling, amyloid pathology and neuroinflammation are closely associated with neurodegenerative disorder like Alzheimer's disease (AD). Our earlier studies showed that intracerebroventricular streptozotocin (STZ) induces insulin receptor (IR) signaling defect in the hippocampus, which is associated with memory impairment in rats. Astrocytes are the most abundant cells in the brain and play a major role in neuroinflammation. ⋯ STZ treatment caused enhanced translocation of p65 NF-kB, triggered over expression of TNF-α, IL-1β, COX-2, oxidative/nitrosative stress and caspase activation (p < 0.05) in astrocytes. Insulin (25-100 nM) pretreatment (n = 3) significantly prevented changes in IR signaling, amyloidogenic protein expression and levels of proinflammatory markers (p < 0.05) in STZ treated astroglial cells. In the present study, the protective effect of insulin suggests that, IR dysfunction along with amyloidogenesis and neuroinflammation may have played a major role in STZ induced toxicity in astrocytes which are relevant to AD pathology.
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Chronic treatment with caffeine, the most widely consumed psychoactive drug and a non-selective antagonist of adenosine receptors, can protection against myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). In this study, we investigated the mechanism underlying caffeine-mediated neuroprotection against EAE by determining the effective therapeutic time-window of caffeine and the involvement of adenosine A2A and A1 receptor. ⋯ The protective effect of chronic caffeine treatment was associated with up-regulation of brain A1R (but not A2AR). The identification of the effective therapeutic window of caffeine at the effector phase and clarification of non-A2AR target (likely A1R) in caffeine action in EAE models advance the therapeutic prospective that chronic caffeine consumption may attenuate brain damage in MS.
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Comparative Study
Lixisenatide, a drug developed to treat type 2 diabetes, shows neuroprotective effects in a mouse model of Alzheimer's disease.
Type 2 diabetes is a risk factor for developing Alzheimer's disease (AD). In the brains of AD patients, insulin signalling is desensitised. The incretin hormone Glucagon-like peptide-1 (GLP-1) facilitates insulin signalling, and analogues such as liraglutide are on the market as treatments for type 2 diabetes. ⋯ The chronic inflammation response (microglial activation) was also reduced by all treatments. The results demonstrate that the GLP-1 receptor agonists liraglutide and lixisenatide which are on the market as treatments for type 2 diabetes show promise as potential drug treatments of AD. Lixisenatide was equally effective at a lower dose compared to liraglutide in some of the parameters measured.
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In addition to analgesia, opioid agonists may increase pain sensitivity under different conditions varying dose and administration pattern. While opioid hyperalgesia induced by tolerance and withdrawal is largely studied, little is known on the mechanisms underlying ultra-low dose morphine hyperalgesia. This pronociceptive response appears to play an opposing role in morphine analgesia and might have clinical relevance. ⋯ No modulation of MAPK and transcription factors' activity was detected in the thalamus. These results support the concept that selective activation of ERK and JNK on descending pathways plays an important role in ultra-low dose morphine hyperalgesia. The modulation of these signalling processes might improve pain management with opiate analgesics.