Cotinine: A Potential New Therapeutic Agent against Alzheimer's disease

Abstract

SUMMARYTobacco smoking has been correlated with a lower incidence of Alzheimer's disease (AD). This negative correlation has been attributed to nicotine's properties. However, the undesired side-effects of nicotine and the absence of clear evidence of positive effects of this drug on the cognitive abilities of AD patients have decreased the enthusiasm for its therapeutic use. In this review, we discuss evidence showing that cotinine, the main metabolite of nicotine, has many of the beneficial effects but none of the negative side-effects of its precursor. Cotinine has been shown to be neuroprotective, to improve memory in primates as well as to prevent memory loss, and to lower amyloid-beta (Aβ)) burden in AD mice. In AD, cotinine's positive effect on memory is associated with the inhibition of Aβ aggregation, the stimulation of pro-survival factors such as Akt, and the inhibition of pro-apoptotic factors such as glycogen synthase kinase 3 beta (GSK3β). Because stimulation of the α7 nicotinic acetylcholine receptors (α7nAChRs) positively modulates these factors and memory, the involvement of these receptors in cotinine's effects are discussed. Because of its beneficial effects on brain function, good safety profile, and nonaddictive properties, cotinine may represent a new therapeutic agent against AD. Alzheimer's disease: The Cholinergic System as a Therapeutic TargetAlzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia [1,2]. The disease is characterized by extracellular accumulation of senile plaques, mainly composed of aggregated forms of the amyloid-beta peptide (Aβ), as well as intracellular accumulation of neurofibrillary tangles of the microtubule-associated protein tau [1]. These neuropathological changes are associated with structural brain abnormalities, inflammation, and cognitive impairment such as impairment of working memory in AD patients. The progressive loss of memory in AD patients correlates with increased levels of Aβ and the deterioration of the cholinergic system in the brain. The degenerative process involves a sequence of pathological events, including early degeneration of the cerebral basal forebrain and subsequent deterioration of the cortical cholinergic system [3,4]. This deterioration commonly includes a reduction in the levels of acetylcholine (ACh) and α3, α4, and α7 nicotinic ACh receptors (nAChRs) as well as a decrease in the activity of choline acetyltranferase in the brain [5].Of these nAChRs, the α7 receptors are considered to be ideal therapeutic targets for several neurological conditions, including AD, schizophrenia, and Parkinson's disease (PD) as well as tobacco addiction [6,7]. The α7nAChR is a homomeric pentamer that has a high permeability to calcium (P Ca :P Na ≈ 10), and undergoes rapid and reversible desensitization and pronounced inward rectification [8]. The α7 subunit is highly expressed in the cortex, hippocampus, and hypothalamus [8], and has also been suggested to have functionally important expression in ...

A review on Alzheimer's disease pathophysiology and its management: an update

“…ANAVEX 2-73 is a mixed muscarinic/s1 359 agonist and is currently in phase I/IIa trials [60]. A few recent 360 studies highlight the use of the metabolite of nicotine ''cotinine'' in 361 cognitive enhancing potential this compound is a positive 362 allosteric modulator of a7 nicotinic AChRs [61].…”

R-(+) and S-(−) Isomers of Cotinine Augment Cholinergic Responses In Vitro and In Vivo

“…Significant evidence from in vitro experiments as well as animal studies suggests that the nicotine metabolite cotinine (1-methyl-5-[3-pyridynl]-2-pyrrolidinone) might have potential as a therapeutic agent for some neurologic and psychiatric disorders, including Alzheimer's disease (AD) and schizophrenia (see reviews in Terry et al, 2005, andZeitlin, 2012). For example, in studies relevant to AD, cotinine has been shown to improve the survival of differentiated PC12 cells deprived of nerve growth factor (Buccafusco and Terry, 2003), as well as primary cortical neurons exposed to toxic concentrations of the amyloid-b peptide or glutamate Gao et al, 2014).…”

A decade of e-cigarettes: Limited research & unresolved safety concerns

“…Alternatively, nicotine has been shown to have beneficial effects on Parkinson’s (Jurado-Coronel et al, 2016; Li et al, 2015; Liu et al, 2015; Lombardo and Maskos, 2015; Quik et al, 2015) and Alzheimer’s disease (Gao et al, 2014; Kem, 2000; Kihara et al, 1997; Xue et al, 2015). Further, nicotine’s major non-addictive metabolite cotinine has been proven to reduce the burden of post-traumatic stress disorder (PTSD) and schizophrenia (SCHZ) (Barreto et al, 2015; Echeverria et al, 2016; Echeverria and Zeitlin, 2012; Echeverria et al, 2011). Perhaps aside from the recreational purpose, e-cigarettes might be reconfigured as efficient nicotine delivery systems (devoid of all the other chemicals and flavoring agents) to treat these disease conditions but extensive preclinical and clinical studies need to be performed to prove substantial therapeutic efficacy.…”