Neuroscience
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C-type natriuretic peptide (CNP) and the natriuretic peptide receptor B (NPR-B) are expressed throughout the hippocampus. We tested whether CNP affected long-term potentiation (LTP) or long-term depression (LTD) in area CA1. Field potentials (FP) were simultaneously recorded in stratum pyramidale (SP) and stratum radiatum (SR) of area CA1 in rat hippocampal slices. ⋯ CNP attenuated LTP in SP and reversed LTP into LTD in SR. These effects were mimicked by low-dose dl-2-amino-5-phosphonopentanoic acid (dl-APV) (10 microM) suggesting partial N-methyl d-aspartate (NMDA) receptor dependency of CNP-mediated effects. Together, our data suggest that CNP is involved in the regulation of bidirectional plasticity in area CA1 potentially by modulating GABA(A)-mediated inhibition and NMDA receptors.
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Nuclear respiratory factor 1 (NRF-1) is one of the key transcription factors implicated in mitochondrial biogenesis by activating the transcription of mitochondrial transcription factor A (mtTFA) and subunit genes of respiratory enzymes. NRF-1 transactivation activity can be enhanced by interaction with transcription coactivator peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha). The expression of PGC-1alpha, NRF-1 and mtTFA in neurons is known to be tightly regulated by neuronal activity. ⋯ Conversely, 1 week of MD significantly reduces AMPK phosphorylation and activity, dramatically down-regulates PGC-1alpha and NRF-1 expression in deprived primary visual cortex. Administration of resveratrol in vivo significantly activates AMPK activity and attenuates the effects of MD on mitochondria by significant increase in PGC-1alpha and NRF-1 levels, mitochondria amount, and coupled respiration. These results strongly indicate that AMPK is an essential upstream mediator that couples neuronal activity to mitochondrial energy metabolism by regulation of PGC-1alpha-NRF-1 pathway in neurons.
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The purposes of this study were to clarify the involvement of P-glycoprotein in the absorption of levosulpiride in knockout mice that lack the Abcb1a/ 1b gene, and to evaluate the relationship between genetic polymorphisms in ABCB1 (exon 12, 21 and 26) and levosulpiride disposition in healthy subjects. The plasma and brain samples were obtained after oral administration (10 microg/g) of levosulpiride to abcb1a/1b(-/-) and wild-type mice (n=3 approximately 6 at each time point). The average brain-to-plasma concentration ratio and blood-brain barrier partitioning of levosulpiride were 2.3- and 2.0-fold higher in Abcb1a/1b(-/-) mice than in wild-type mice, respectively. ⋯ The subjects were evaluated for polymorphisms of the ABCB1 exon 12 C1236T, exon 21 G2677A/T (Ala893Ser/Thr) and exon 26 C3435T using polymerase chain reaction restriction fragment length polymorphism. The PK parameters (AUC(0-4h), AUC(0-infinity) and C(max.)) of ABCB1 2677TT and 3435TT subjects were significantly higher than those of subjects with at least one wild-type allele (P<0.05). The results indicate that levosulpiride is a P-glycoprotein substrate in vivo, which is supported by the effects of SNPs 2677G>A/T in exon 21 and 3435C>T in exon 26 of ABCB1 on levosulpiride disposition.
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The panglial syncytium maintains ionic conditions required for normal neuronal electrical activity in the central nervous system (CNS). Vital among these homeostatic functions is "potassium siphoning," a process originally proposed to explain astrocytic sequestration and long-distance disposal of K(+) released from unmyelinated axons during each action potential. Fundamentally different, more efficient processes are required in myelinated axons, where axonal K(+) efflux occurs exclusively beneath and enclosed within the myelin sheath, precluding direct sequestration of K(+) by nearby astrocytes. ⋯ If any of several molecular components of the panglial syncytium are compromised, K(+) siphoning is blocked, myelin is destroyed, and axonal saltatory conduction ceases. Thus, a common thread linking several CNS demyelinating diseases is the disruption of potassium siphoning/water transport within the panglial syncytium. Continued progress in molecular identification and subcellular mapping of glial ion and water channels will lead to a better understanding of demyelinating diseases of the CNS and to development of improved treatment regimens.
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Although malfunction of spinal cord water channels (aquaporins, AQP) likely contributes to severe disturbances in ion/water homeostasis after spinal cord injury (SCI), their roles are still poorly understood. Here we report and discuss the potential significance of changes in the AQP4 expression in human SCI that generates glial fibrillary acidic protein (GFAP)-labeled astrocytes devoid of AQP4, and GFAP-labeled astroglia that overexpress AQP4. We used a rat model of contusion SCI to study observed changes in human SCI. ⋯ We found that AQP4 increases in the chronic post-injury phase are associated with the development of pain-like behavior in SCI rats, while possible mechanisms underlying pain development may involve astrocytic swelling-induced glutamate release. In contrast, the formation and size of fluid-filled cavities occurring later after SCI does not appear to be affected by the extent of increased AQP4 levels. Therefore, the effect of therapeutic interventions targeting AQP4 will depend not only on the time interval after SCI or animal models, but also on the balance between protective role of increased AQP4 in hypoxia and deleterious effects of ongoing astrocytic swelling.