3,6'-Dithiothalidomide, a new TNF-? synthesis inhibitor, attenuates the effect of A?1-42 intracerebroventricular injection on hippocampal neurogenesis and memory deficit.

ABSTRACT: Evidence indicates altered neurogenesis in neurodegenerative diseases associated with inflammation, including Alzheimer's 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)-? 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-? lowering drug, 3,6'-dithiothalidomide, on hippocampal progenitor cell proliferation, neurogenesis and, memory tasks after intracerebroventricular injection of ?-amyloid (Aß)(1-42) peptide. Seven days after A?(1-42) injection, a significant proliferation of hippocampal progenitor cells and memory impairment were evident. Four weeks after A?(1-42) 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?(1-42) provoked effects. Our data indicate that although treatment with 3,6'-dithiothalidomide in part attenuated the increase in hippocampal neurogenesis caused by A?(1-42) -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?(1-42) 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.

SUBMITTER: Russo I 

PROVIDER: S-EPMC4608365 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature