Neurotoxicity research
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Neurotoxicity research · Feb 2010
General anesthesia causes long-lasting disturbances in the ultrastructural properties of developing synapses in young rats.
Common general anesthetics administered to young rats at the peak of brain development cause widespread apoptotic neurodegeneration in their immature brain. Behavioral studies have shown that this leads to learning and memory deficiencies later in life. The subiculum, a part of the hippocampus proper and Papez's circuit, is involved in cognitive development and is vulnerable to anesthesia-induced developmental neurodegeneration. ⋯ We found that this anesthesia, when administered at the peak of synaptogenesis, causes long-lasting injury to the subicular neuropil. This is manifested as neuropil scarcity and disarray, morphological changes indicative of mitochondria degeneration, a decrease in the number of neuronal profiles with multiple synaptic boutons and significant decreases in synapse volumetric densities. We believe that observed morphological disturbances of developing synapses may, at least in part, contribute to the learning and memory deficits that occur later in life after exposure of the immature brain to general anesthesia.
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Neurotoxicity research · Feb 2010
Valproic acid is neuroprotective in the rotenone rat model of Parkinson's disease: involvement of alpha-synuclein.
Valproic acid (VPA), an established antiepileptic and antimanic drug, has recently emerged as a promising neuroprotective agent. Among its many cellular targets, VPA has been recently demonstrated to be an effective inhibitor of histone deacetylases. Accordingly, we have adopted a schedule of dietary administration (2% VPA added to the chow) that results in a significant inhibition of histone deacetylase activity and in an increase of histone H3 acetylation in brain tissues of 4 weeks-treated rats. ⋯ Furthermore, monoubiquitinated alpha-synuclein increased its localization in nuclei isolated from substantia nigra of rotenone-treated rats, an effect also prevented by VPA treatment. Nuclear localization of alpha-synuclein has been recently described in some models of PD and its neurodegenerative effect has been ascribed to histone acetylation inhibition. Thus, the ability of VPA to increase histone acetylation is a novel candidate mechanism for its neuroprotective action.
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Neurotoxicity research · Feb 2010
Endoplasmic reticulum stress plays critical role in brain damage after cerebral ischemia/reperfusion in rats.
The endoplasmic reticulum(ER) stress plays a vital role in mediating ischemic neuronal cell death. However, very little is known about the role of ER stress in mediating pathophysiological reactions to acute brain injuries. An attempt was therefore made to assess the role of cerebral ischemia/reperfusion (I/R) induced ER stress and its modulation on outcome of ischemic insult. ⋯ The enhanced expression of GRP78, Caspase-12, CHOP/GADD153, ATF4 and processing of xbp1 mRNA in the affected brain regions clearly indicate the critical involvement of ER-mediated cell death/survival mechanisms and also collectively demonstrated the activation of unfolded protein response (UPR). Moreover, Salubrinal, a selective inhibitor of eIF2alpha dephosphorylation was used to counteract ER stress, which significantly increased the phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (eIF2alpha), leading to reduced brain damage after I/R injury. Therefore, inhibition of ER stress following I/R injury may be used as key therapeutic target for neuroprotection.