TNF-α protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation

Journal of Neuroinflammation

Susanna Rosi¹  Nigel H Greig²  Weiming Luo²  Carla Arellano³  David Tweedie²  Timothy Jopson³  Karim Belarbi³ 

[1] Brain and Spinal Injury Center, University of California San Francisco, San Francisco General Hospital, 1001 Potrero Ave, Bld#1, Room#101 94110, San Francisco, CA, USA;Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA;Departments of Physical Therapy Rehabilitation Science and Neurological Surgery, University of California, San Francisco, California, USA

关键词: Tumor necrosis factor-α;    Learning and memory;    Inflammation;    Immediate-early gene;    Hippocampus;    Arc;   

Others  :  1212834
DOI  :  10.1186/1742-2094-9-23

 received in 2011-11-29, accepted in 2012-01-25,  发布年份 2012

【 摘 要 】

Background

Chronic 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.

Methods

Lipopolysaccharide 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.

Results

Chronic 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.

Conclusion

Our 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.

【 授权许可】

   
2012 Belarbi et al; licensee BioMed Central Ltd.

【 图 表 】

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