Abstract
BackgroundChronic neuroinflammation is a hallmark of several neurological disorders associated with cognitive loss. Activated microglia and secreted factors such as tumor necrosis factor (TNF)-α are key mediators of neuroinflammation and may contribute to neuronal dysfunction. Our study was aimed to evaluate the therapeutic potential of a novel analog of thalidomide, 3,6'-dithiothalidomide (DT), an agent with anti-TNF-α activity, in a model of chronic neuroinflammation.MethodsLipopolysaccharide or artificial cerebrospinal fluid was infused into the fourth ventricle of three-month-old rats for 28 days. Starting on day 29, animals received daily intraperitoneal injections of DT (56 mg/kg/day) or vehicle for 14 days. Thereafter, cognitive function was assessed by novel object recognition, novel place recognition and Morris water maze, and animals were euthanized 25 min following water maze probe test evaluation.ResultsChronic LPS-infusion was characterized by increased gene expression of the proinflammatory cytokines TNF-α and IL-1β in the hippocampus. Treatment with DT normalized TNF-α levels back to control levels but not IL-1β. Treatment with DT attenuated the expression of TLR2, TLR4, IRAK1 and Hmgb1, all genes involved in the TLR-mediated signaling pathway associated with classical microglia activation. However DT did not impact the numbers of MHC Class II immunoreactive cells. Chronic neuroinflammation impaired novel place recognition, spatial learning and memory function; but it did not impact novel object recognition. Importantly, treatment with DT restored cognitive function in LPS-infused animals and normalized the fraction of hippocampal neurons expressing the plasticity-related immediate-early gene Arc.ConclusionOur data demonstrate that the TNF-α synthesis inhibitor DT can significantly reverse hippocampus-dependent cognitive deficits induced by chronic neuroinflammation. These results suggest that TNF-α is a critical mediator of chronic neuroinflammation-induced neuronal dysfunction and cognitive impairment and targeting its synthesis could provide an effective therapeutic approach to several human neurodegenerative diseases.
Highlights
Chronic neuroinflammation is a hallmark of several neurological disorders associated with cognitive loss
Treatment with 3,6’-dithiothalidomide normalized tumor necrosis factor (TNF)-a but not IL-1b levels TNF-a expression in the hippocampus was assessed at the transcript level using real time PCR analysis
Our findings suggest that the decrease of TNF-a led to an attenuated expression of genes involved within the TLRmediated signaling pathway associated with classical microglia activation
Summary
Chronic neuroinflammation is a hallmark of several neurological disorders associated with cognitive loss. Microglia activation is present during the early stages of many neurodegenerative conditions, such as Alzheimer’s disease, Parkinson’s disease and HIV-associated dementia [1,2,3]. TNF-a is generated as a transmembrane 26-kDa precursor molecule that is proteolytically cleaved to yield a soluble 17kDa TNF-a protein that subsequently generates a noncovalently linked homotrimer in solution Both membrane-bound and soluble forms of TNF-a are biologically active, signaling through two different transmembrane spanning receptor (R) subtypes, TNF-R1 and TNF-R2. Elevated levels of TNF-a have been documented in several neurodegenerative disorders including Alzheimer’s disease [21,22,23,24], Parkinson’s disease [25,26] and HIV-associated dementia [27]. The regulation of TNF-a signaling may prove to be beneficial in the context of neurodegenerative disorders associated with neuroinflammation [28]
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