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1.
Drug Discov Today Technol ; 10(3): e329-42, 2013 Sep.
Article in English | MEDLINE | ID: mdl-24179995

ABSTRACT

In chronic diseases such as Alzheimer's disease (AD), the arsenal of biomarkers available to determine the effectiveness of symptomatic treatment is very limited. Interpretation of the results provided in literature is cumbersome and it becomes difficult to predict their standardization to a larger patient population. Indeed, cognitive assessment alone does not appear to have sufficient predictive value of drug efficacy in early clinical development of AD treatment. In recent years, research has contributed to the emergence of new tools to assess brain activity relying on innovative technologies of imaging and electrophysiology. However, the relevance of the use of these newer markers in treatment response assessment is waiting for validation. This review shows how the early clinical assessment of symptomatic drugs could benefit from the inclusion of suitable pharmacodynamic markers. This review also emphasizes the importance of re-evaluating a step-by-step strategy in drug development.


Subject(s)
Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Animals , Biomarkers, Pharmacological , Humans , Treatment Outcome
2.
J Pharmacol Exp Ther ; 332(2): 505-14, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19889791

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.


Subject(s)
Alzheimer Disease/drug therapy , Imipramine/therapeutic use , Memory Disorders/drug therapy , Memory/drug effects , Neuroprotective Agents/therapeutic use , Tumor Necrosis Factor-alpha/metabolism , Amyloid beta-Peptides/administration & dosage , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/antagonists & inhibitors , Amyloid beta-Protein Precursor/metabolism , Animals , Cognition/drug effects , Disease Models, Animal , Frontal Lobe/drug effects , Frontal Lobe/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Imipramine/pharmacology , Injections, Intraventricular , Male , Memory Disorders/chemically induced , Mice , Neuroprotective Agents/pharmacology , Peptide Fragments/antagonists & inhibitors , Peptide Fragments/pharmacology
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