RGD Reference Report - TNF-alpha protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation. - Rat Genome Database

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

Authors: Belarbi, K  Jopson, T  Tweedie, D  Arellano, C  Luo, W  Greig, NH  Rosi, S 
Citation: Belarbi K, etal., J Neuroinflammation. 2012 Jan 25;9:23. doi: 10.1186/1742-2094-9-23.
RGD ID: 7495794
Pubmed: PMID:22277195   (View Abstract at PubMed)
PMCID: PMC3298520   (View Article at PubMed Central)
DOI: DOI:10.1186/1742-2094-9-23   (Journal Full-text)

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)-alpha 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-alpha 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-alpha and IL-1beta in the hippocampus. Treatment with DT normalized TNF-alpha levels back to control levels but not IL-1beta. 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-alpha synthesis inhibitor DT can significantly reverse hippocampus-dependent cognitive deficits induced by chronic neuroinflammation. These results suggest that TNF-alpha 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cognitive disorder treatmentISOIrak1 (Rattus norvegicus)7495794; 7495794 RGD 
cognitive disorder treatmentIEP 7495794 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Irak1  (interleukin-1 receptor-associated kinase 1)

Genes (Mus musculus)
Irak1  (interleukin-1 receptor-associated kinase 1)

Genes (Homo sapiens)
IRAK1  (interleukin 1 receptor associated kinase 1)


Additional Information