Flavio M. Morais, Pollyanna V.G. Silva and Angela M. Ribeiro*
Background: Data obtained by our group and by other authors directed our interest towards better understanding the involvement of the GABArgic and glutamatergic systems in the neurodegenerative process. We began a more in-depth search into this subject and came across various apparently contradictory data, most likely from the use of different experimental models and measurement conditions. We therefore considered it relevant to carry out a systematic review followed by a meta-analysis of the results, with the aim of answering contradictory questions about the involvement and importance of components of these two systems in the neurodegeneration process associated with AD and PD. There is no systematic survey in the literature aimed at verifying the relevance and degree of significance of the relationships between GABAergic and glutamatergic parameters and the neurodegeneration phenomenon observed in these diseases.
Method: We gathered and analyzed the data obtained from various studies published in the PubMed and Scopus databases between 1987 and 2024, in which the authors measured molecular parameters in samples obtained post-mortem from patients and in experimental models (rodents). The study was divided into two stages. The first stage focused on neurodegenerative processes in a more general way. In this phase, studies were selected in which the measurements were carried out on total brain samples and therefore without specifying the region. The partial analysis of the data obtained in the first stage showed a predominance of studies addressing AD and PD and, in addition, indicated significant effects on decreasing GABA levels. To further explore this result, we decided to add to the keywords of the first stage, the specification of brain regions generally affected in these two conditions and found in studies selected in the first stage. This included the regions of the neocortex, hippocampus, striatum and PAG.
Results: The main findings of the meta-analysis, testing for the overall effect, were that GABA levels in AD are significantly lower in the neocortex of rodents (Z=2.50; p-value=0.01) and humans (Z=3.49; p-value=0.0005) and in the hippocampus of rodents (Z=3.91; p-value<0.0001). This data, decreased GABA was also observed in human whole brain samples (Z=3.66; p-value=0.0003). GABA-A receptor expression was higher in the neocortex (Z=2.47; p-value=0.01) and hippocampus (Z=2.49; p-value=0.01) of affected individuals (rodents). On the other hand, glutamate levels were not affected in either of these two regions, neocortex and hippocampus, in rodents. In Parkinson's disease, GABA levels were lower in the striatum (Z=2.53; p-value=0.01) and PAG (Z=2.59; p-value =0.009) of affected individuals. Unlike AD, there was no difference in GABA levels in the neocortex in humans. There were no differences in glutamate levels in the striatum and neocortex.
Conclusion: based on the data presented here, we found that the literature provides an inconclusive overview of changes in GABA levels and GABAergic components in the brain areas of patients with AD and PD, and therefore grouping the data using the meta-analysis method represents an important contribution of the present study. The data corroborate recent evidence that the original descriptions of neurodegenerative diseases as being mainly due to lesions in dopaminergic systems in the midbrain for PD and hippocampal cholinergic and glutamatergic lesions for AD and other dementias should be updated within a concept of multisystem neurodegeneration, where a progressive functional decline of the GABAergic system needs to be further considered and better studied.
Published Date: 2025-10-21; Received Date: 2024-07-10
