Molecular neurobiology
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Molecular neurobiology · Oct 2015
Early Exposure to General Anesthesia Disrupts Spatial Organization of Presynaptic Vesicles in Nerve Terminals of the Developing Rat Subiculum.
Exposure to general anesthesia (GA) during critical stages of brain development induces widespread neuronal apoptosis and causes long-lasting behavioral deficits in numerous animal species. Although several studies have focused on the morphological fate of neurons dying acutely by GA-induced developmental neuroapoptosis, the effects of an early exposure to GA on the surviving synapses remain unclear. The aim of this study is to study whether exposure to GA disrupts the fine regulation of the dynamic spatial organization and trafficking of synaptic vesicles in presynaptic terminals. ⋯ In addition to a significant decrease in the density of presynaptic vesicles, we observed a reduction of docked vesicles, as well as a reduction of vesicles located within 100 nm from the active zone, in animals 5 days after an initial exposure to GA. We also found that the synaptic vesicles of animals exposed to GA are located more distally with respect to the plasma membrane than those of sham control animals and that the distance between presynaptic vesicles is increased in GA-exposed animals compared to sham controls. We report that exposure of immature rats to GA during critical stages of brain development causes significant disruption of the strategic topography of presynaptic vesicles within the nerve terminals of the subiculum.
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Molecular neurobiology · Aug 2015
The Neuroprotection of Lysosomotropic Agents in Experimental Subarachnoid Hemorrhage Probably Involving the Apoptosis Pathway Triggering by Cathepsins via Chelating Intralysosomal Iron.
α-Lipoic acid-plus (LAP), an amine derivative of α-lipoic acid (LA), could protect cells against oxidant challenges via chelating intralysosomal iron. However, the application of LAP in experimental subarachnoid hemorrhage (SAH) is still not well known. This study was designed to evaluate the potential neuroprotection of LAP on the early brain injury (EBI) and the underlying mechanisms in a rat model of SAH. ⋯ Furthermore, LA and LAP significantly ameliorated brain edema, blood-brain barrier injury, cortical apoptosis, and neurological behavior impairment induced by SAH. Finally, it is noteworthy that LAP exerted more significant effects than LA on these parameters as described above. LAP probably exerted neuroprotective effects via targeting lysosomes and chelating intralysosomal iron in EBI post-SAH in rats.
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Molecular neurobiology · Apr 2015
Loss of phenotype of parvalbumin interneurons in rat prefrontal cortex is involved in antidepressant- and propsychotic-like behaviors following acute and repeated ketamine administration.
Accumulating evidence has demonstrated that single subanesthetic dose of ketamine exerts rapid, robust, and lasting antidepressant-like effects. Nevertheless, repeated subanesthetic doses of ketamine produce psychosis-like effects with dysfunction of parvalbumin (PV) interneurons. We hypothesized that PV interneurons play an important role in the antidepressant-like actions of ketamine, and different changes in PV interneurons occur with the antidepressant-like and propsychotic-like effects of ketamine. ⋯ Repeated administration of 30 mg/kg ketamine elicited stereotyped behaviors and hyperactivity actions as well as a longer duration of PV and GAD67 loss, higher brain glutamate levels, and lower brain GABA levels than acute single dose of ketamine. Our results reveal that the loss of phenotype of PV interneurons in the prefrontal cortex contributes to the antidepressant-like actions and is also involved in the propsychotic-like behaviors following acute and repeated ketamine administration, which may be partially mediated by the disinhibition of glutamate signaling. The different degrees and durations of the actions on PV interneurons produced by the two regimens of ketamine may partly underline the behavioral variance between the antidepressant- and propsychotic-like effects.
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Molecular neurobiology · Apr 2015
ReviewSpecific binding of lacosamide to collapsin response mediator protein 2 (CRMP2) and direct impairment of its canonical function: implications for the therapeutic potential of lacosamide.
The novel antiepileptic drug lacosamide (LCM; SPM927, Vimpat®) has been heralded as having a dual-mode of action through interactions with both the voltage-gated sodium channel and the neurite outgrowth-promoting collapsin response mediator protein 2 (CRMP2). Lacosamide's ability to dampen neuronal excitability through the voltage-gated sodium channel likely underlies its efficacy in attenuating the symptoms of epilepsy (i.e., seizures). While the role of CRMP2 in epilepsy has not been well studied, given the proposed involvement of circuit reorganization in epileptogenesis, the ability of lacosamide to alter CRMP2 function may prove disease modifying. ⋯ In this review, we address the contradictory reports concerning the binding of lacosamide to CRMP2 as well as the ability of lacosamide to directly impact CRMP2 function. Additionally, we address similarly the contradicting reports regarding the potential disease-modifying effect of lacosamide on the development and progression of epilepsy. As the vast majority of antiepileptic drugs influences only the symptoms of epilepsy, the ability to hinder disease progression would be a major breakthrough in efforts to cure or prevent this debilitating syndrome.
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Molecular neurobiology · Feb 2015
Pathway analysis of two amyotrophic lateral sclerosis GWAS highlights shared genetic signals with Alzheimer's disease and Parkinson's disease.
Amyotrophic lateral sclerosis (ALS) is the third most common neurodegenerative disease after Alzheimer's disease (AD) and Parkinson's disease (PD). In order to unravel more genetic etiology of ALS, genome-wide association studies (GWAS) have been conducted. However, the newly identified ALS susceptibility loci exert only very small risk effects and cannot fully explain the underlying ALS genetic risk. ⋯ We compared the findings from ALS GWAS with those of previous pathway analyses of AD and PD GWAS. The results further supported the involvement of AD and PD risk pathways in ALS. We believe that our results may advance the understanding of ALS mechanisms and will be very useful for future genetic studies.