Imipramine, in Part through Tumor Necrosis Factor α Inhibition, Prevents Cognitive Decline and β-Amyloid Accumulation in a Mouse Model of Alzheimer's Disease

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 332; no. 2; p. 505
• Main Authors: F. Chavant, J. Deguil, S. Pain, I. Ingrand, S. Milin, B. Fauconneau, M.-C. Pérault-Pochat, C. Lafay-Chebassier
• Format: Journal Article
• Language: English
• Published: American Society for Pharmacology and Experimental Therapeutics 01.02.2010
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.109.162164

Alzheimer's disease (AD), the most common form of dementia in the older people, is a multifactoral pathology, characterized by cognitive deficits, increase in cerebral deposition of the β-amyloid (Aβ) peptide, neurofibrillary tangles, and neurodegeneration. Studies currently support a central role of neuroinflammation, through production of proinflammatory cytokines including excess tumor necrosis factor α (TNF-α) in the pathogenesis of AD, especially in Aβ-induced cognitive deficits. Imipramine, a tricyclic antidepressant, has potent anti-inflammatory and neuroprotective effects. This study investigates the effect of imipramine on alterations of long-term and short-term memories, TNF-α expression, and amyloid precursor protein (APP) processing induced by intracerebroventricular injection of Aβ25-35 in mice. Mice were treated with imipramine (10 mg/kg i.p. once a day for 13 days) from the day after the Aβ25-35 injection. Memory function was evaluated in the water-maze (days 10–14) and Y-maze (day 9) tests. TNF-α levels and APP processing were examined in the frontal cortex and the hippocampus (day 14). Imipramine significantly prevented memory deficits caused by Aβ25-35 in the water-maze and Y-maze tests, and inhibited the TNF-α increase in the frontal cortex. Moreover, imipramine decreased the elevated levels of Aβ both in frontal cortex and hippocampus with different modulations of APP and C-terminal fragments of APP. So, imipramine prevents memory impairment through its intrinsic property to inhibit TNF-α and Aβ accumulation and may represent a potential candidate for AD treatment.