3,6′-Dithiothalidomide, a new TNF-α synthesis inhibitor, attenuates the effect of Aβ1-42 intracerebroventricular injection on hippocampal neurogenesis and memory deficit

J. Neurochem. (2012) 122, 11811192. Abstract Evidence indicates altered neurogenesis in neurodegenerative diseases associated with inflammation, including Alzheimers disease (AD). Neuroinflammation and its propagation have a critical role in the degeneration of hippocampal neurons, cognitive impairment, and altered neurogenesis. Particularly, tumor necrosis factor (TNF)-a plays a central role in initiating and regulating the cytokine cascade during an inflammatory response and is up-regulated in brain of AD patients. In this study, we investigated the effects of a novel thalidomide-based TNF-a lowering drug, 3,6'-dithiothalidomide, on hippocampal progenitor cell proliferation, neurogenesis and, memory tasks after intracerebroventricular injection of beta-amyloid (A beta)142 peptide. Seven days after A beta 142 injection, a significant proliferation of hippocampal progenitor cells and memory impairment were evident. Four weeks after A beta 142 peptide injection, elevated numbers of surviving 5-bromo-2'-deoxyuridine cells and newly formed neurons were detected. Treatment with 3,6'-dithiothalidomide attenuated these A beta 142 provoked effects. Our data indicate that although treatment with 3,6'-dithiothalidomide in part attenuated the increase in hippocampal neurogenesis caused by A beta 142-induced neuroinflammation, the drug prevented memory deficits associated with increased numbers of activated microglial cells and inflammatory response. Therefore, 3,6'-dithiothalidomide treatment likely reduced neuronal tissue damage induced by neuroinflammation following A beta 142 injection. Understanding the modulation of neurogenesis, and its relationship with memory function could open new therapeutic interventions for AD and other neurodegenerative disorders with an inflammatory component.