A New Tacrine–Melatonin Hybrid Reduces Amyloid Burden and Behavioral Deficits in a Mouse Model of Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is a progressive degenerative disorder characterized by the presence of amyloid deposits, neurofibrillary tangles and neuron loss. Emerging evidence indicates that antioxidants could be useful either for the prevention or treatment of AD. Tacrine and melatonin are well-known drugs which act as an acetylcholinesterase inhibitor and a free radical scavenger, respectively. In this study, we evaluated the effects of a new tacrine-melatonin hybrid on behavior and the biochemical and neuropathologic changes observed in amyloid precursor protein/presenilin 1 (APP/Ps1) transgenic mice. Our findings showed that direct intracerebral administration of this hybrid decreased amyloid beta peptide (Abeta)-induced cell death and amyloid burden in the brain parenchyma of APP/Ps1 mice. This reduction in Abeta pathology was accompanied by a recovery in cognitive function. Since this tacrine-melatonin hybrid apparently reduces brain Abeta and behavioral deficits, we believe this drug has remarkable and significant neuroprotective effects and might be considered a potential therapeutic strategy in AD.

Synthesis and Multitarget Biological Profiling of a Novel Family of Rhein Derivatives As Disease-Modifying Anti-Alzheimer Agents

“…65,66 However, different families of anti-Alzheimer hybrid compounds with molecular weights over 500 have shown good oral availability and/or brain permeability in ex vivo and in vivo studies in mice. 12,40,67,68 Even though the potential of a CNS drug to enter into the brain also depends on a low P-glycoprotein efflux liability, 69,70 a good brain permeability is a necessary requirement. In this work, the brain permeability of the novel rhein-huprine hybrids has been predicted through the widely known parallel artificial membrane permeation assay (PAMPA-BBB).…”

Melatonin plus physical exercise are highly neuroprotective in the 3xTg-AD mouse

“…Treatment with the hormone melatonin has also been reported to be neuroprotective in AD mouse models (Matsubara et al, 2003;Feng et al, 2004;Olcese et al, 2009;Spuch et al, 2010).…”

Therapeutical Implications of Melatonin in Alzheimer’s and Parkinson’s Diseases

“…These hybrids showed better antioxidant-and cholinergicpreserving activity tacrine or melatonin alone. The direct intracerebral administration of one of these hybrids decreased induced cell death and Aß load in the APP/ PS1 mouse brain parenchyma accompanied by a recovery of cognitive function (Spuch et al 2010 ).…”

“…Melatonin inhibited lipopolysaccharide-and streptozotocin-induced increase in AChE activity (Agrawal et al 2009 ). Recently hybrids of the AChE inhibitor tacrine and melatonin were synthesized as new drug candidates for treating AD (Fernandez-Bachiller et al 2009 ;Spuch et al 2010 ). These hybrids showed better antioxidant-and cholinergicpreserving activity tacrine or melatonin alone.…”