Neuroscience
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Comparative Study
Neuronal expression of the drug efflux transporter P-glycoprotein in the rat hippocampus after limbic seizures.
In the brain, the efflux transporter P-glycoprotein (Pgp) is predominantly located on the luminal membrane of endothelial cells lining brain microvessels and forming the blood-brain barrier. Many lipophilic drugs, including antiepileptic drugs, are potential substrates for Pgp. Overexpression of Pgp in endothelial cells of the blood-brain barrier has been determined in patients with drug resistant forms of epilepsy such as temporal lobe epilepsy and rodent models of temporal lobe epilepsy and suggested to lead to reduced penetration of antiepileptic drugs into the brain. ⋯ No neuronal Pgp staining was seen in control rats. The expression of Pgp in neurons after limbic seizures was substantiated by determining Pgp encoding genes (mdr1a, mdr1b) in neurons by real time quantitative RT-PCR. Increased Pgp expression in hippocampal neurons is likely to affect the action of drugs with intraneuronal targets and, in view of recent evidence from other cell types, could be associated with prevention of apoptosis which is involved in neuronal damage developing after seizures such as produced by pilocarpine.
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Prevention of neuronal apoptosis has been introduced as a new therapeutic strategy for neurodegenerative disorders. We have previously reported anti-apoptotic effects of transforming growth factor-beta1 (TGF-beta1), a multifunctional cytokine, in models of cerebral ischemia and in cultured neurons and recently focused on the mechanisms underlying the anti-apoptotic effect of TGF-beta1. The anti-apoptotic transcriptional factor nuclear factor kappa B (NF-kappaB) shows high impact in the cell survival function of multiple cytokines and growth factors. ⋯ TGF-beta1 produced a concomitant increase in the phosphorylations of Ikappabeta kinase (IKKalpha/beta) and Ikappabetaalpha with a subsequent degradation of Ikappabetaalpha. Interestingly, the increased phosphorylation of IKKalpha/beta and Ikappabetaalpha was abrogated by wortmannin, but not by U0126, suggesting that PI3k/Akt and MAPK/Erk1,2 pathways triggered by TGF-beta1 regulated the activation of NF-kappabeta through different mechanisms. Of note, wortmannin and U0126, as well as kappabeta-decoy DNA, abolished the anti-apoptotic effect of TGF-beta1, corroborating the notion that both PI3k/Akt and MAPK/Erk1,2 pathways, and NF-kappabeta activity are necessary for the anti-apoptotic activity of TGF-beta1.
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Comparative Study
Initiation of electrographic seizures by neuronal networks in entorhinal and perirhinal cortices in vitro.
The hippocampus is often considered to play a major role in the pathophysiology of mesial temporal lobe epilepsy. However, emerging clinical and experimental evidence suggests that parahippocampal areas may contribute to a greater extent to limbic seizure initiation, and perhaps epileptogenesis. To date, little is known about the participation of entorhinal and perirhinal networks to epileptiform synchronization. ⋯ These procedures also shortened ictal discharge duration in the entorhinal cortices, but not in the perirhinal area. Similar results could be obtained by applying Mg(2+)-free medium (n=7). These findings indicate that parahippocampal networks provide independent epileptiform synchronization sufficient to sustain limbic seizures as well as that the perirhinal cortex plays a preferential role in in vitro ictogenesis.
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Comparative Study
Mouse strains that lack spinal dynorphin upregulation after peripheral nerve injury do not develop neuropathic pain.
Several experimental models of peripheral neuropathy show that a significant upregulation of spinal dynorphin A and its precursor peptide, prodynorphin, is a common consequence of nerve injury. A genetically modified mouse strain lacking prodynorphin does not exhibit sustained neuropathic pain after nerve injury, supporting a pronociceptive role of elevated levels of spinal dynorphin. A null mutation of the gamma isoform of protein kinase C (PKCgamma KO [knockout]), as well as an inbred mouse strain, 129S6, also does not manifest behavioral signs of neuropathic pain following peripheral nerve injury. ⋯ However, the PKCgamma KO mice and the 129S6 mice (which express PKCgamma) did not show abnormal pain after SNL; neither strain showed elevated levels of spinal dynorphin. The multiple phenotypic deficits in PKCgamma KO mice confound the interpretation of the proposed role of PKCgamma-expressing spinal neurons in neuropathic pain states. Additionally, the data show that the regulation of spinal dynorphin expression is a common critical feature of expression of neuropathic pain.
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Comparative Study
Motor balance and coordination training enhances functional outcome in rat with transient middle cerebral artery occlusion.
The goal of this study was to determine if relatively complex motor training on Rota-rod involving balance and coordination plays an essential role in improving motor function in ischemic rats, as compared with simple locomotor exercise on treadmill. Adult male Sprague-Dawley rats with (n=40) or without (n=40) ischemia were trained under each of three conditions: (1) motor balance and coordination training on Rota-rod; (2) simple exercise on treadmill; and (3) non-trained controls. Motor function was evaluated by a series of tests (foot fault placing, parallel bar crossing, rope and ladder climbing) before and at 14 or 28 days after training procedures in both ischemic and normal animals. ⋯ E.), treadmill (45+/-5%) or non-exercised control (45+/-3%). In addition, no obvious difference could be detected in the location of the damage which included the dorso-lateral portion of the neostriatum and the frontoparietal cortex, the main regions supplied by the middle cerebral artery. The data suggest that complex motor training rather than simple exercise effectively improves functional outcome.