ABSTRACT
Alcohol-related cognitive impairment (ARCI) is highly prevalent among patients with alcohol abuse and dependence. The pathophysiology of ARCI, pivotal for refined therapeutic approaches, is not fully elucidated, posing a risk of progression to severe neurological sequelae such as Korsakoff's syndrome (KS) and Alcohol-Related Dementia (ARD). This study ventures into the underlying mechanisms of chronic alcohol-induced neurotoxicity, notably glutamate excitotoxicity and cytoskeletal disruption, and explores the therapeutic potential of Memantine, a non-competitive antagonist of the N-methyl-d-aspartate (NMDA) receptor known for its neuroprotective effect against excitotoxicity. Our investigation centers on the efficacy of Memantine in mitigating chronic alcohol-induced cognitive and hippocampal damages in vivo. Male C57BL/6J mice were subjected to 30 % (v/v, 6.0 g/kg) ethanol via intragastric administration alongside Memantine co-treatment (10 mg/kg/day, intraperitoneally) for six weeks. The assessment involved Y maze, Morris water maze, and novel object recognition tests to evaluate spatial and recognition memory deficits. Histopathological evaluations of the hippocampus were conducted to examine the extent of alcohol-induced morphological changes and the potential protective effect of Memantine. The findings reveal that Memantine significantly improves chronic alcohol-compromised cognitive functions and mitigates hippocampal pathological changes, implicating a moderating effect on the disassembly of actin cytoskeleton and microtubules in the hippocampus, induced by chronic alcohol exposure. Our results underscore Memantine's capability to attenuate chronic alcohol-induced cognitive and hippocampal morphological harm may partly through regulating cytoskeleton dynamics, offering valuable insights into innovative therapeutic strategies for ARCI.
Subject(s)
Cognitive Dysfunction , Disease Models, Animal , Hippocampus , Memantine , Mice, Inbred C57BL , Animals , Memantine/pharmacology , Male , Mice , Hippocampus/drug effects , Hippocampus/pathology , Hippocampus/metabolism , Cognitive Dysfunction/drug therapy , Ethanol/toxicity , Ethanol/administration & dosage , Neuroprotective Agents/pharmacology , Neuroprotective Agents/administration & dosage , Alcoholism/drug therapy , Alcoholism/pathology , Alcoholism/complications , Maze Learning/drug effects , Excitatory Amino Acid Antagonists/pharmacology , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/metabolismABSTRACT
BACKGROUND: Alcohol abuse, a prevalent global health issue, is associated with the onset of cognitive impairment and neurodegeneration. Actin filaments (F-actin) and microtubules (MTs) polymerized from monomeric globular actin (G-actin) and tubulin form the structural basis of the neuronal cytoskeleton. Precise regulation of the assembly and disassembly of these cytoskeletal proteins, and their dynamic balance, play a pivotal role in regulating neuronal morphology and function. Nevertheless, the effect of prolonged alcohol exposure on cytoskeleton dynamics is not fully understood. This study investigates the chronic effects of alcohol on cognitive ability, neuronal morphology and cytoskeleton dynamics in the mouse hippocampus. METHODS: Mice were provided ad libitum access to 5% (v/v) alcohol in drinking water and were intragastrically administered 30% (v/v, 6.0 g/kg/day) alcohol for six weeks during adulthood. Cognitive functions were then evaluated using the Y maze, novel object recognition and Morris water maze tests. Hippocampal histomorphology was assessed through hematoxylin-eosin (HE) and Nissl staining. The polymerized and depolymerized states of actin cytoskeleton and microtubules were separated using two commercial assay kits and quantified by Western blot analysis. RESULTS: Mice chronically exposed to alcohol exhibited significant deficits in spatial and recognition memory as evidenced by behavioral tests. Histological analysis revealed notable hippocampal damage and neuronal loss. Decreased ratios of F-actin/G-actin and MT/tubulin, along with reduced levels of polymerized F-actin and MTs, were found in the hippocampus of alcohol-treated mice. CONCLUSIONS: Our findings suggest that chronic alcohol consumption disrupted the assembly of the actin cytoskeleton and MTs in the hippocampus, potentially contributing to the cognitive deficits and pathological injury induced by chronic alcohol intoxication.
Subject(s)
Actin Cytoskeleton , Ethanol , Hippocampus , Microtubules , Animals , Hippocampus/drug effects , Hippocampus/metabolism , Hippocampus/pathology , Microtubules/drug effects , Microtubules/metabolism , Actin Cytoskeleton/drug effects , Actin Cytoskeleton/metabolism , Male , Ethanol/pharmacology , Ethanol/administration & dosage , Mice , Mice, Inbred C57BL , Central Nervous System Depressants/pharmacology , Central Nervous System Depressants/administration & dosage , Disease Models, Animal , Behavior, Animal/drug effectsABSTRACT
This case reports a 35-year-old man who presented with a painful erythematous nodule on his right posterior calf. He first noticed this nodule several years ago and it often bled upon contact with clothing. An excisional biopsy of the skin lesion revealed two distinct populations of cells. One population of epithelioid cells stained positive for Mart-1, HMB45, and SOX-10, confirming the diagnosis of malignant melanoma. The second population of cells stained positive for desmin and calponin, confirming the diagnosis of sarcoma with muscular differentiation. Subsequently, these unusual findings led to the diagnosis of a collision tumor comprising malignant melanoma and rhabdomyosarcoma. Follow-up PET/CT and brain MRI revealed no metastasis from the primary skin lesion. This case highlights a rare combination of cell types found within a collision tumor in addition to providing details on how to diagnose this skin lesion.