Following traumatic brain injury (TBI) there is significant neuropathology which includes mitochondrial dysfunction, loss of cortical grey matter, microglial activation, and cognitive impairment. Previous evidence has shown that activation of the peroxisome proliferator-activated receptors (PPARs) provide neuroprotection following traumatic brain and spinal injuries. In the current study we hypothesized that treatment with the PPAR ligand Pioglitazone would promote neuroprotection following a rat controlled cortical impact model of TBI. Animals received a unilateral 1.5mm controlled cortical impact followed by administration of pioglitazone at 10mg/kg beginning 15 minutes after the injury and subsequently every 24hrs for five days. Beginning one day after the injury there was significant impairment in mitochondrial bioenergetic function which was attenuated by treatment with Pioglitazone at 15 minutes and 24 hours (p<0.05). In an
ATP-sensitive potassium channels (KATP) play a crucial role in coupling metabolic energy to the membrane potential of cells, thereby functioning as cellular "metabolic sensors." Recent evidence has showed a connection between the amyloid neurotoxic cascade and metabolic impairment. With regard to their neuroprotection in other neuronal preparations, KATP channels may mediate a potential neuroprotective role in Alzheimer's disease (AD). To investigate the effects of Abeta1-42 on the subunits of KATP expression in cultured primary rat basal forebrain cholinergic neurons, primary rat basal forebrain neurons were cultured and evaluated. The subunits of KATP: Kir6.1, Kir6.2, SUR1 and SUR2 expressing changes were observed by double immunofluorescence and immunoblotting when the neurons were exposed to Abeta1-42(2 microM) for different time (0, 24, 72 h). We found a significant increase in the expression of Kir6.1 and SUR2 in the cultured neurons being exposed to Abeta1-42 for 24 h, while Kir6.2 and SUR1 showed no significant change. However, after being treated with Abeta1-42 for 72 h, the expression of the four subunits was all increased significantly compared with the control. These findings suggest that being exposed to Abeta1-42 for different time (24 and 72 h) induces differential regulations of KATP subunits expression in cultured primary rat basal forebrain cholinergic neurons. The change in composition of KATP may contribute to resist the toxicity of Abeta1-42.
The ATP-sensitive potassium channel (KATP) play a crucial role in coupling metabolic energy to the cell membrane potential, β-amyloid peptide (Aβ) neurotoxicity has been associated with cellular oxidative stress and metabolic impairment. Whether there is an interaction between KATP and Aβ or not? The expression of KATP subunits was to be investigated after the cultured primary rat basal forebrain cholinergic neurons being exposed to Aβ₁₋₄₂. The subunits of KATP: Kir6.1, Kir6.2, SUR1 and SUR2 expressing change was observed by double Immunofluorescence and immunoblotting in cultured cholinergic neurons from different groups: treatment with Aβ₁₋₄₂ (group Aβ₁₋₄₂), pretreatment with diazoxide and then exposure to Aβ₁₋₄₂ (group diazoxide + Aβ₁₋₄₂), and the control (group control). The results showed that in response to the treatment with Aβ₁₋₄₂ (2 μmol/L) for 24 h, the expression of Kir6.1 and SUR2 were significantly up-regulated, while this change can be partly reversed by pretreatment with diazoxide (1 mmol/L) for 1 h. There were significant increases in all KATP subunits expression levels after exposure to Aβ₁₋₄₂ for 72 h. However, the up-regulation of Kir6.1, Kir6.2 and SUR2 except SUR1 can be partly reversed by pretreatment with diazoxide (1 mmol/L) for 1 h. It is concluded that exposure to Aβ₁₋₄₂ for different time (24 and 72 h) induced differential regulation of KATP subunits expression in cultured primary rat basal forebrain cholinergic neurons. The change in composition of KATP may contribute to the dysfunction of KATP and membrane excitability disturbance. The effect of diazoxide on KATP subunits expression may explain, in part, the resistance of diazoxide to the toxicity of Aβ₁₋₄₂.
The present research demonstrates that activation of MitoKATP channels independently or in combination with inhibitors of the MTP can elicit a protective effect against primary cholinergic neuron cytotoxicity induced by A-beta1-42. These findings suggest new mitochondrial targets for the development of therapeutic agents against A-beta-induced cytotoxicity.
It is concluded that Abeta(1-42) inhibits the openings of the K(ATP) channels, while this inhibitory action can be removed by pretreatment with Diazoxide. It is indicated that the opening of K(ATP) channels may play a potential neuroprotective role in antineurotoxicity of Abeta(1-42), and the application of Diazoxide in small dose may be helpful in the treatment of Abeta(1-42) neurotoxicity.
Purpose To evaluate the effect of a single intravenous low-dose esketamine combined with labour analgesia on the occurrence of postpartum depression in patients with spontaneous labour.Methods Female patients in labour were divided into a group of esketamine combined with labour analgesia (group A, n = 116), a group with labour analgesia alone (group B, n = 132) and a control group (group C, n = 51) according to the mode of analgesia. The Edinburgh Postpartum Depression Scale (EPDS) and visual analog scale (VAS) scores were collected at different time points for all three groups. Serum was also collected from patients before and after delivery to detect serum sex hormone changes.Results This clinical study was a prospective, randomised, double-blind trial. A total of 299 patients were enrolled in the study. Cross-sectional analysis showed no significant differences in EPDS scores or incidence of depression between the three groups in postpartum period, or at 1, 7 or 42 days postpartum. There were no statistically significant differences in VAS scores at 2 hours postpartum, 1 day, 2 days and 7 days postpartum. No significant differences were seen in the levels of oestrogen, progesterone, 5hydroxytryptamine and serum cortisol before delivery between the three groups. After delivery, serum cortisol levels were higher in the labour analgesia alone group than in the esketamine combined with labour analgesia group and the control group (P < 0.001). Longitudinal analysis showed that EPDS and VAS scores improved significantly over time in postpartum period for both combined esketamine and labour analgesia alone (P < 0.001), but no significant change was seen in the control group. This improvement was possibly associated with a decrease in postpartum oestrogen levels and an increase in serum cortisol levels (P < 0.001).Conclusion In this study, the combination of esketamine with labour analgesia did not reduce the incidence of depression and VAS scores at 1, 7 or 42 days postpartum.
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