Neuroscience
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We have recently documented that treatment with the alternative biofuel, acetyl-L-carnitine (ALC, 300 mg/kg), as late as 1 h after T10 contusion spinal cord injury (SCI), significantly maintained mitochondrial function 24 h after injury. Here we report that after more severe contusion SCI centered on the L1/L2 segments that are postulated to contain lamina X neurons critical for locomotion (the "central pattern generator"), ALC treatment resulted in significant improvements in acute mitochondrial bioenergetics and long-term hind limb function. ⋯ These findings signify that functional improvements with ALC treatment are mediated, in part, by preserved locomotor circuitry rostral to upper lumbar contusion SCI. Based on beneficial effects of ALC on mitochondrial bioenergetics after injury, our collective evidence demonstrate that preventing mitochondrial dysfunction acutely "promotes" neuroprotection that may be associated with the milestone recovery of plantar, weight-supported stepping.
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The production of otoacoustic emissions (OAEs) by the cochlea is a sexually dimorphic trait. Although often hypothesized to be influenced by testosterone in utero, little attention has been devoted to the possibility that levels of circulating sex steroids in adulthood might modulate the sex difference in OAE production. The purpose of the current study was to investigate whether oral contraceptive (OC) use affects OAE production in women, revisiting a question originally posed by McFadden [(2000) Hearing Research 142:23-33]. ⋯ Two types of OAEs were quantified: those produced spontaneously (spontaneous otoacoustic emissions or SOAEs) and those produced in response to click stimuli (click-evoked otoacoustic emissions or CEOAEs). Women currently using OCs showed a defeminized pattern of OAE production: they produced fewer SOAEs, SOAEs with significantly less power, and smaller CEOAE response amplitudes compared with naturally cycling women who were tested irrespective of phase of the menstrual cycle. It is proposed that the observed group difference may be mediated by the interaction of circulating estradiol with estrogen receptor alpha (ERα) or estrogen receptor beta (ERβ) receptors in the cochlea.
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Dysregulation in brain-derived neurotrophic factor (BDNF)/full-length TrkB (TrkB-TK+) signaling is implicated in promoting neurodegeneration in Alzheimer's disease (AD). BDNF/TrkB-TK+ signaling can be modulated by the presence of truncated TrkB isoforms (TrkB-TK-, TrkB-Shc). All TrkB isoforms are encoded by different alternative transcripts. ⋯ Interestingly, TrkB-Shc overexpression selectively attenuated BDNF/TrkB-TK+-mediated signaling via the mitogen-activated protein kinase kinase (MEK) pathway, but not the protein kinase B pathway. In AD, MEK signaling is increased in vulnerable neurons and linked to abnormal phosphorylation of cytoskeletal proteins. Altogether, our findings suggest that elevated TrkB-Shc expression in AD may function as a compensatory response in neurons in AD to promote survival.
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We tested the hypothesis that the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway mediates some of the neuroprotective effects of progesterone (PROG) after ischemic stroke. We examined whether PROG acting through the PI3K/Akt pathway could affect the expression of vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF). Rats underwent permanent focal cerebral ischemia by electrocoagulation and received intraperitoneal injections of PROG (8 mg/kg) or vehicle at 1 h post-occlusion and subcutaneous injections at 6, 24, and 48 h. ⋯ The treatment also increased BDNF, and attenuated apoptosis by increasing Akt phosphorylation compared with vehicle alone. The selective PI3K inhibitor wortmannin compromised PROG-induced neuroprotective effects and reduced the elevation of pAkt levels in the ischemic penumbra. Our findings lead us to suggest that the PI3K/Akt pathway can play a role in mediating the neuroprotective effects of PROG after stroke by altering the expression of trophic factors in the brain.
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Studies using animal models have shown that general anesthetics such as ketamine trigger widespread and robust apoptosis in the infant rodent brain. Recent clinical evidence suggests that the use of general anesthetics on young children (at ages equivalent to those used in rodent studies) can promote learning deficits as they mature. Thus, there is a growing need to develop strategies to prevent this injury. ⋯ In separate studies, pretreatment of P6 animals with 20 mg/kg vitamin D(3) or a nontoxic dose of ketamine (5 mg/kg) also prevented ketamine-induced apoptosis at P7. In contrast, pretreatment of P7 animals with aspirin (30 mg/kg) 15 min before ketamine administration actually increased AC3 counts in some regions. These data show that a number of unique approaches can be taken to address anesthesia-induced neurotoxicity in the infant brain, thus providing MDs with a variety of alternative strategies that enhance therapeutic flexibility.