Neuroscience
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Persistent activation of GABAA receptors triggers compensatory changes in receptor function that are relevant to physiological, pathological and pharmacological conditions. Chronic treatment of cultured neurons with GABA for 48h has been shown to produce a down-regulation of receptor number and an uncoupling of GABA/benzodiazepine site interactions with a half-time of 24-25h. Down-regulation is the result of a transcriptional repression of GABAA receptor subunit genes and depends on activation of L-type voltage-gated calcium channels. ⋯ Together, these data suggest that the uncoupling mechanism involves an initial increase in receptor internalization followed by activation of a signaling cascade that leads to selective changes in receptor subunit levels. These changes might result in the assembly of receptors with altered subunit compositions that display a lower degree of coupling between GABA and benzodiazepine sites. Uncoupling might represent a homeostatic mechanism that negatively regulates GABAergic transmission under physiological conditions in which synaptic GABAA receptors are transiently activated for several minutes.
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Our previous study demonstrated that chronic prenatal methamphetamine (MA) exposure and a single dose of MA in adulthood decrease focally induced epileptiform activity in adult male rats. As seizures are known to be dependent on sex and female estrous cycle, the goal of the present study was to examine the combined effect of prenatal MA exposure (5mg/kg) and the MA challenge dose (1mg/kg) in adulthood on electroencephalography (EEG) recordings and consequences of brain stimulation in freely moving adult female rats with respect to the estrous cycle. Overall, 12 groups of adult female rats were tested: prenatally MA-exposed, prenatally saline-exposed and rats without prenatal injections, each of these groups was either postnatally challenged with MA or with saline injection (MA-MA, MA-S; S-MA, S-S; C-MA, C-S) and further divided according to the stage of the estrous cycle to metestrus/diestrus (M/D) or proestrus/estrus (P/E). ⋯ The challenge dose of MA also decreased the seizure threshold. Moreover, prenatal as well as adult MA administration decreased the number and occurrence of WDS, respectively. Thus, the present study demonstrates that the effect of prenatal MA exposure and challenge dose of the same drug on focally induced epileptiform activity in adult female rats depends on the estrous cycle.
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Clinical studies have shown that agonist-antagonist opioid analgesics that produce their analgesic effect via action on the kappa-opioid receptor, produce a delayed-onset anti-analgesia in men but not women, an effect blocked by co-administration of a low dose of naloxone. We now report the same time-dependent anti-analgesia and its underlying mechanism in an animal model. Using the Randall-Selitto paw-withdrawal assay in male rats, we found that nalbuphine, pentazocine, and butorphanol each produced analgesia during the first hour followed by anti-analgesia starting at ∼90min after administration in males but not females, closely mimicking its clinical effects. ⋯ The selective NOP receptor antagonists, JTC801, and J-113397, but not the sigma receptor antagonist, BD 1047, antagonized nalbuphine anti-analgesia. Furthermore, the NOP receptor agonist NNC 63-0532 produced anti-analgesia with the same delay in onset observed with the three agonist-antagonists, but without producing preceding analgesia and this anti-analgesia was also blocked by naloxone. These results strongly support the suggestion that clinically used agonist-antagonists act at the NOP receptor to produce anti-analgesia.
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Pro-inflammatory cytokines induced by inflammation and iron accumulation in the substantia nigra (SN) have been implicated in the pathogenesis of Parkinson's disease (PD). In the present study, we aimed to investigate the relationship between inflammation and iron accumulation in a lipopolysaccharide (LPS)-induced Parkinsonian rat model. The activation of glial cells and elevated levels of pro-inflammatory cytokines were observed in the SN of LPS models, accompanied by iron deposits in the same region. ⋯ The expression of heme oxygenase-1 (HO-1) was also upregulated in vivo and in vitro. These results suggested that pro-inflammatory cytokines might induce Fpn downregulation, which leads to iron accumulation and dopaminergic neurons' degeneration in PD. HO-1 may also contribute to the iron accumulation in neurons, but its mechanism needs to be further investigated.
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Angiogenin is a member of the ribonuclease superfamily and promotes degradation of the basement membrane and the extracellular matrix. After stroke in type one diabetes (T1DM) rats, Angiogenin is significantly increased and the Angiogenin is inversely correlated with functional outcome. Neamine, an aminoglycoside antibiotic, blocks nuclear translocation of Angiogenin, thereby abolishing the biological activity of Angiogenin. In this study, we therefore investigated the effect and underlying protective mechanisms of Neamine treatment of stroke in T1DM. ⋯ Neamine treatment of stroke is neuroprotective in T1DM rats. Inhibition of neuroinflammatory factor expression and decrease of BBB leakage may contribute to Neamine-induced neuroprotective effects after stroke in T1DM rats.