Morphological Investigation of Alcohol and Drug-Related Changes in the Central Nervous System. Summary of the Doctoral Thesis

Abstract

Psychoactive substances-induced damage causes dysfunction of selected brain regions. Alcohol and addictive substances and their associated oxidative stress are widespread contributors to the brain damage. Matrix metalloproteinases (MMP), involved in the cleavage of extracellular matrix (ECM) proteins, are extensively analyzed in brain pathology studies. However, MMPs have not been sufficiently investigated in cases of chronic alcohol and drug consumption. Results, demonstrated recently, showed involvement of multifunctional inductive factors in CNS changes caused by alcohol and drug addiction. This study attempted to elucidate a preferential cellular vulnerability in different brain regions of chronic alcoholics and drug users, structurally and ultrastructurally. Brain tissue autopsy material obtained from the cortex cerebri, corpus striatum and substantia nigra as well as the liver tissue of 46 alcoholic subjects and 10 drug users was studied. A role of MMP9 in the injury and remodeling of extracellular space of brain via mediating cleavage of ECM components was specified in this study. Alcoholics and drug users revealed statistically significant elevation of neuronal MMP9 expression in all brain regions studied. Further evidence on the putative correlation between the brain damage in alcoholics and drug users, up-regulation of oxidative stress marker superoxide dismutase-1 (SOD1) and MMP9 expression were obtained. We found correlation between neuronal expression patterns of SOD1 and MMP9 in nigral (r=0.532, p<0.001), striatal (r=0.327, p<0.001), and cortical (r=0.306, p<0.001) regions. Contribution of MMP9 to these alterations was evidenced in alcoholics and drug users and correlated with ultrastructural changes. We demonstrated that oxidative stress caused by alcohol is one of the most important contributors to the changes of endogenous antioxidant system and protective reactivity of neural and hepatic constituents reflected by cytoskeleton, mitochondria, and intracellular membranes changes. In this study, immunohistochemically assessed heterogeneous expression of inductive factors was determined in the cortex cerebri and substantia nigra regions and correlated with results obtained by electron microscopy examination. Neuronal cells and glial cells of the gray matter demonstrated the strongest TUNEL reaction positivity in the corpus striatum. We found that neuronal somata do not display irreversible changes, evident in dendritic tree and glial cells. We suggest that these behavior differences are related to the selective response to alcohol and drug addiction-induced injury in the central nervous system. This selective reaction was proven by a decrease of SOD1 immunoreactivity in the white matter of the substantia nigra was accompanied by severe damage of myelin structure revealed electron microscopically. Energy dispersive spectroscopy can be used for carbon and oxygen peak identification in brain samples. Elements such as phosphorus, sulfur and calcium presented in lower concentrations, can be captured in brain samples as well. Moreover, changes of calcium concentrations related to different brain structures can be assessed by energy dispersive spectroscopy. The study was elaborated with a support of ESF project “Support for doctoral and post-doctoral investigations Riga Stradins University” (Nr. 2009/0147/1DP/1.1.2.1.2/09/IPIA/VIAA/009).