title: Imipramine, in part through tumor necrosis factor alpha inhibition, prevents cognitive decline and beta-amyloid accumulation in a mouse model of Alzheimer's disease.
abstract: 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 beta-amyloid (Abeta) peptide, neurofibrillary tangles, and neurodegeneration. Studies currently support a central role of neuroinflammation, through production of proinflammatory cytokines including excess tumor necrosis factor alpha (TNF-alpha) in the pathogenesis of AD, especially in Abeta-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-alpha expression, and amyloid precursor protein (APP) processing induced by intracerebroventricular injection of Abeta25-35 in mice. Mice were treated with imipramine (10 mg/kg i.p. once a day for 13 days) from the day after the Abeta25-35 injection. Memory function was evaluated in the water-maze (days 10-14) and Y-maze (day 9) tests. TNF-alpha levels and APP processing were examined in the frontal cortex and the hippocampus (day 14). Imipramine significantly prevented memory deficits caused by Abeta25-35 in the water-maze and Y-maze tests, and inhibited the TNF-alpha increase in the frontal cortex. Moreover, imipramine decreased the elevated levels of Abeta 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-alpha and Abeta accumulation and may represent a potential candidate for AD treatment.
authors.affiliation: Groupe de Recherche sur le Vieillissement Cérébral-Equipe d'accueil 3808, Université de Poitiers, Poitiers, France.
authors.forename: F
authors.initials: F
authors.lastname: Chavant
authors.forename: J
authors.initials: J
authors.lastname: Deguil
authors.forename: S
authors.initials: S
authors.lastname: Pain
authors.forename: I
authors.initials: I
authors.lastname: Ingrand
authors.forename: S
authors.initials: S
authors.lastname: Milin
authors.forename: B
authors.initials: B
authors.lastname: Fauconneau
authors.forename: M-C
authors.initials: MC
authors.lastname: Pérault-Pochat
authors.forename: C
authors.initials: C
authors.lastname: Lafay-Chebassier
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D003071:Cognition / Q000187:drug effects; D004195:Disease Models, Animal; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology / Q000627:therapeutic use*; D007276:Injections, Intraventricular; D008297:Male; D008568:Memory / Q000187:drug effects*; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy*; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; D007099:Imipramine