Neuroprotective effects of n-acetylcysteine in an acute model of LPS induced neuroinflammation

Neuroinflammation has been a major focus for researchers in the fields of neurology and neuropathology, as it had proven to play a key role in triggering the pathogenesis of various neurodegenerative diseases like Alzheimer's disease, where inflammation, among many other interconnected factors including oxidative stress and mitochondrial dysfunction plays a crucial role in the pathological feedback loop contributing to disease progression. Therefore, there is an inevitable need for implicating variable models of neuroinflammation, and it remains promising to investigate potential therapeutics, those of a natural origin in particular. LPS induced neuroinflammation is a widely used model in animal research and is able to mimic intrinsic neuroinflammatory states seen in the human CNS by activating microglia and initiating the release of several proinflammatory cytokines. Numerous studies have pointed out the relevance of glial cells, like astrocytes and microglia to neuroinflammation, thus to possibly linked protein abnormalities like Tau fibrillary tangles and amyloid plaques. Moreover, recent works are focusing on the microglial activation derived perineuronal net disruptions in neurodegenerative and neuropsychiatric disorders. These disruptions might hold the answer to understanding the vulnerability of particular neuronal types to neuroinflammation. In this project, we investigated the neuroprotective role of N-Acetylcysteine, a well-known natural antioxidant, on an acute, 10-day model of centrally injected LPS rats. Animal Groups consisted of healthy controls, LPS-induced animals, NAC treated LPS-induced and a group treated with an additional prophylactic dose of NAC prior to model induction. We assessed the anti-inflammatory potential of NAC in terms of neuronal loss, perineuronal net degradation, glial cell activation, and protein aggregations, in addition to cognitive decline, using immunofluorescence stainings, ELISA and a behavioral test for working memory. Our results indicated that NAC was able to reduce LPS-induced Aβ1–42 accumulations in the brain and spinal cord, as well as to halt neuronal loss and inflammatory astrocytosis in variable regions of the hippocampus. Moreover, NAC administration clearly protected PNN structures and alleviated PNN density loss associated with LPS-induced microglial activation in the prefrontal cortex. These results indicate the potential neuroprotective and anti-inflammatory impact of NAC on early neuroinflammation-associated CNS pathologies and highlight the need for more in-depth investigation regarding the neuro-protective role of NAC in models of inflammatory neurodegeneration.