title: TNF-α protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Brain and Spinal Injury Center, University of California, San Francisco, California, USA.
authors.forename: Karim
authors.initials: K
authors.lastname: Belarbi
authors.forename: Timothy
authors.initials: T
authors.lastname: Jopson
authors.forename: David
authors.initials: D
authors.lastname: Tweedie
authors.forename: Carla
authors.initials: C
authors.lastname: Arellano
authors.forename: Weiming
authors.initials: W
authors.lastname: Luo
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
authors.forename: Susanna
authors.initials: S
authors.lastname: Rosi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D004660:Encephalitis / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005106:Exploratory Behavior / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006624:Hippocampus / Q000473:pathology; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009483:Neuropsychological Tests; D011134:Polysaccharides / Q000633:toxicity; D051381:Rats; D011916:Rats, Inbred F344; D021641:Recognition, Psychology / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013028:Space Perception / Q000187:drug effects; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C562075:3,6'-dithiothalidomide; D051017:Apoptosis Regulatory Proteins; D004791:Enzyme Inhibitors; D000949:Histocompatibility Antigens Class II; D011134:Polysaccharides; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide