GLUCOSE SUPPLEMENTATION SUPPORTS THE NEUROPROTECTIVE EFFECT OF SYNAPTIC SILENCING DURING INFLAMMATORY NEURODEGENERATION

Upon recognition of pathogens or other inflammatory stimuli, microglia are rapidly activated to efficiently limit the damage and to restore homeostasis. However, dysregulated or chronic microglia activation might trigger severe network disruption and neurodegeneration. Whether such disrupted network activity itself contributes to neurodegenerative processes remains unclear. Our hypothesis is that proinflammatory microglia drive pathological network activity, which in turn exacerbates neuronal metabolic and oxidative stress.
Rat organotypic hippocampal slice cultures were exposed to IFNγ (interferonγ) plus the TLR4 ligand LPS (lipopolysaccharide) to induce a highly activated microglia phenotype, including neuronal network dysfunction and neurodegeneration. A blocker cocktail (TTX, CNQX, D-AP5) was applied to silence synaptic transmission during microglia activation, while glucose availability was manipulated to assess the contribution of metabolic support. Local field potential (LFP) recordings, biochemical assays—including LDH (cell death marker), nitric oxide (NO; Griess reaction) and proinflammatory cytokines TNF-α and IL-6 (ELISA)— and immunostaing were performed.
LFP revealed a significant reduction in slice cultures showing no activity when the blocker cocktail was present during IFNγ+LPS exposure. Interestingly, an enhanced neuroprotection was observed when glucose concentration was increased in the culture medium, suggesting that glucose supplementation further preserves neuronal network function under inflammatory stress. Despite increased NO levels, LDH and IL-6 release decreased significantly, whereas TNF-α release remained unchanged. Immunostaining showed wide preservation of parvalbumin-positive GABAergic interneurons that are highly vulnerable to metabolic and oxidative stress in inflammatory damage. Our findings highlight the importance of metabolic support and suppression of neuronal hyperexcitability in inflammatory neurodegeneration.