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4 An abnormal apical dendrite (a) from a pyramidal neuron in the FCx and an abnormal axon (a) from the Strt (both from P21 PEE male offspring). Both processes show a clear corkscrewlike appearance. Note in a, inside the dendrite, one mitochondria with an unusual Y-bifurcated shape. A normal axon from the Strt of control animals (c) and two amplified portions (d,e) from the axon depicted in b, showing a disorganized cytoskeleton. Images in c-e were digitally inverted to their negative form for a better visualization of the cytoskeleton. Primary amplification: a: 7000×; b: 5000×; c-e: 31500×. (Modified from Evrard, 2008)
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Ethanol (EtOH) is the most ancient drug and one of those most used and abused by human beings. Although its effects are better
known and are best studied on the cytoskeleton of hepatocytes (due to the EtOH role in the etiology of liver cirrhosis), its
effects on nerve tissue cells’ cytoskeleton are beginning to be elucidated. We review in this chap...
Citations
... The common comorbidity of alcoholism with other neuropsychiatric disorders led us to investigate whether there was overlapping molecular damage to the PFC in alcoholic patients, and alcoholics that had committed suicide, when compared to their corresponding age-and sex-matched controls (Demographic Tables 1 and 2). From both mRNA and proteomic studies, regional and heterogeneous reductions of microtubule (MT) and microtubule-associated protein (MAP) expressions have also been reported within the mammalian brain in response to alcohol exposures [10,34,35]. To extend these studies, we have focused upon expression of the αand β-tubulin proteins and MAPs in human alcoholic and suicide alcoholic cohorts. ...
Repetitive excessive alcohol intoxication leads to neuronal damage and brain shrinkage. We examined cytoskeletal protein expression in human post-mortem tissue from Brodmann's area 9 of the prefrontal cortex (PFC). Brain samples from 44 individuals were divided into equal groups of 11 control, 11 alcoholic, 11 non-alcoholic suicides, and 11 suicide alcoholics matched for age, sex, and post-mortem delay. Tissue from alcoholic cohorts displayed significantly reduced expression of α-and β-tubulins, and increased levels of acetylated α-tubulin. Protein levels of histone deacetylase-6 (HDAC6), and the microtubule-associated proteins MAP-2 and MAP-tau were reduced in alcoholic cohorts, although for MAPs this was not significant. Tubulin gene expressions increased in alcoholic cohorts but not significantly. Brains from rats administered alcohol for 4 weeks also displayed significantly reduced tubulin protein levels and increased α-tubulin acetylation. PFC tissue from control subjects had reduced tubulin protein expression that was most notable from the sixth to the eighth decade of life. Collectively, loss of neuronal tubulin proteins are a hallmark of both chronic alcohol consumption and natural brain ageing. The reduction of cytosolic tubulin proteins could contribute to the brain volumetric losses reported for alcoholic patients and the elderly.
... The damaging effects of EtOH on the central nervous system (CNS) has drawn much attention recently, and EtOH has been found to have profound effects in altering the structure and function of the CNS [38]. A rise in intracellular Ca 2? and subsequent aberrant Ca 2? homeostasis may be one of the mechanisms involved in EtOHinduced damage of the CNS. ...
Long-term exposure of ethanol (EtOH) alters the structure and function in brain and spinal cord. The present study addresses the mechanisms of EtOH-induced damaging effects on spinal motoneurons in vitro. Altered morphology and biochemical changes of such damage were demonstrated by in situ Wright staining and DNA ladder assay. EtOH at low to moderate (25-50 mM) concentrations induced damaging effects in the motoneuronal scaffold which involved activation of proteases like μ-calpain and caspase-3. Caspase-8 was seen only at higher (100 mM) EtOH concentration. Further, pretreatment with calpeptin, a potent calpain inhibitor, confirmed the involvement of active proteases in EtOH-induced damage to motoneurons. The lysosomal enzyme cathepsin D was also elevated in the motoneurons by EtOH, and this effect was significantly attenuated by inhibitor treatment. Overall, EtOH exposure rendered spinal motoneurons vulnerable to damage, and calpeptin provided protection, suggesting a critical role of calpain activation in EtOH-induced alterations in spinal motoneurons.
... The cytoskeleton of nerve tissue cells is substantially altered by PEE (see Evrard and Brusco, 2011 for a comprehensive review). We showed that cytoskeletal proteins in neurons and glia are changed by exposure to both low ( Ramos et al., 2002;Evrard et al., 2003Evrard et al., , 2006) and high EtOH concentrations ( Aronne et al., 2008). ...
Cannabinoid receptor type 1 (CB1R) modulates synaptic activity and is widely distributed in brain areas such as the hippocampus, cerebellum, cerebral cortex, and striatum, among others. CB1R is involved in processes such as memory, learning, motor coordination, and mood. Genetic deletion of CB1R causes behavioral alterations. In this work, we evaluated neuronal morphology and synaptic structure in the hippocampus of adult male CB1R knockout mice (CB1R−/−). Morphological changes in the CB1R−/− hippocampus evidenced a decrease in the expression of cytoskeletal proteins neurofilaments 160 KDa, neurofilaments 200 KDa, and microtubule‐associated protein 2. CA1 neurons showed decreased arborization and changes in synaptic structure such as lower thickness of postsynaptic density and a reduction in synaptophysin levels. Results obtained in the present work provide evidence of the participation of CB1R in the establishment of neuronal structure and networks that could have an important role in neuronal plasticity. In addition, these changes observed in CB1R−/− could be correlated with behavioral alterations reported. CB1R knockout mice showed decreased neuronal dendritic arborization and changes in synaptic structure, as such as lower thickness of postsynaptic density and a reduction in synaptophysin levels in hippocampus.
The deleterious effects of ethanol (EtOH) on the brain have been widely described, but its effects on the neuronal cytoskeleton during differentiation have not yet been firmly established. In this context, our aim was to investigate the direct effect of EtOH on cortical neurons during the period of differentiation. Primary cultures of cortical neurons obtained from 1-day-old rats were exposed to EtOH after 7days of culture, and viability and morphology were analyzed at structural and ultrastructural levels after 24-h EtOH exposure. EtOH caused a significant reduction of 73±7% in the viability of cultured cortical neurons, by preferentially inducing apoptotic cellular death. This effect was accompanied by an increase in caspase 3 and 9 expression. Furthermore, EtOH induced a reduction in total dendrite length and in the number of dendrites per cell. Ultrastructural studies showed that EtOH increased the number of lipidic vacuoles, lysosomes and multilamellar vesicles and induced a dilated endoplasmatic reticulum lumen and a disorganized Golgi apparatus with a ring-shape appearance. Microtubules showed a disorganized distribution. Apposition between pre- and postsynaptic membranes without a defined synaptic cleft and a delay in presynaptic vesicle organization were also observed. Synaptophysin and PSD95 expression, proteins pre- and postsynaptically located, were reduced in EtOH-exposed cultures. Overall, our study shows that EtOH induces neuronal apoptosis and changes in the cytoskeleton and membrane proteins related with the establishment of mature synapses. These direct effects of EtOH on neurons may partially explain its effects on brain development.
The cytoskeleton is involved in the control of key cellular processes in nervous system development and maintenance, such as cell division, cell migration, cell differentiation, intracellular transport, and structural support. Its disruption by the interaction of neurotoxins with core proteins or with cytoskeletal regulatory systems can therefore be detrimental to a wide range of phenomena including neural development. There is a growing body of evidence for the induction of developmental neurotoxicity via disruption of cell signaling and cytoskeleton-dependent physiological processes by several groups of chemicals including organophosphorus esters (OPs), heavy metals, polybrominated diphenyl ethers (PBDEs), and solvents. This chapter focuses on evidence from studies showing that cytoskeletal disruption following exposure to such compounds may disrupt neural development, thereby supporting the notion that cytoskeletal disruption may represent a useful biomarker of developmental neurotoxicity.
Rats with pre-hepatic portal hypertension because of partial portal vein ligation develop minimal hepatic encephalopathy (MHE) with hyperammonemia, impaired blood-brain barrier, mild brain edema, and severe mitochondrial changes in the hippocampus. The aim of this study was to evaluate changes of different neural cells in the cerebral cortex and the hippocampus. Animals were divided into two groups, MHE and sham. Astrocytes were studied by immunostaining with glial fibrillary acidic protein and S100β protein; neurons were immunostained with neuronal nuclear marker, microtubule associated protein-2, and NF-200 and capillaries with Nestin. The hypoxia-inducible factor 1α (HIF-1α) and its downstream proteins, P-glycoprotein (P-gp) and erythropoietin receptor (Epo-R), were also evaluated. Astrocytes were increased in area and number only in the hippocampus, while S100β increased in both brain areas in MHE animals. Microtubule associated protein-2 and NF-200 immunoreactivities (-ir) were significantly reduced in both areas. Hippocampal Nestin-ir was increased in MHE animals. These cellular changes were similar to those described in ischemic conditions, thus HIF-1α, P-gp, and Epo-R were also evaluated. A high expression of HIF-1α in cortical neurons was observed in the MHE group. It is likely that this hypoxia-like state is triggered via ammonia occupying the binding domain of HIF-1α and thereby preventing its degradation and inducing its stabilization, leading to the over-expression of P-gp and the Epo-R.
