Nicotinic Receptor Modulation for Neuroprotection and Enhancement of Functional Recovery Following Brain Injury or Disease

Abstract

Despite the well-known adverse health effects of tobacco smoking, numerous studies have shown that nicotine, the principal pharmacologically active alkaloid in tobacco smoke, exerts neuroprotective properties in several animal models of neurodegeneration. Furthermore, cigarette smoking appears to significantly reduce the risk of developing Parkinson's disease in human subjects. We review the animal and human studies that investigated possible neuroprotective actions of nicotine and other nicotinic receptor agonists and antagonists. We demonstrate that nicotine is not neuroprotective in all animal models of neurodegenerative disease. In fact, C57Bl/6 mice pretreated with nicotine have an increased sensitivity to 3-nitropropionic acid, a neurotoxin used in mice to mimic some aspects of Huntington's disease. The actions of nicotine on dopamine release may explain the variable effects of nicotine in animal models of Parkinson's and Huntington's diseases. Finally, we focus on some future directions for studies that evaluate neuroprotective properties of nicotinic agonists and antagonists.

Novel perspectives of neural stem cell differentiation: From neurotransmitters to therapeutics

“…Moreover, clinical data suggests their involvement in the pathogenesis of several disorders such as Alzheimer's disease (71), schizophrenia (72), Parkinson's disease (73), autoimmune autonomic neuropathy (74), and hereditary epilepsies (75). In this context, neuroprotective actions of nAChRs have been very well characterized (76). However, nicotine-exerted functions on developing neurons have not yet been thoroughly investigated.…”

Neuronal nicotinic acetylcholine receptor expression and function on nonneuronal cells

“…While this fi nding is controversial, there is now ample evidence supporting a therapeutic benefi t from nicotine in Parkinson ' s 5 disease, and as a neuroprotectant to toxic insults such as excitotoxins [6][7][8][9][10] or Beta-amyloid derived peptides. [10][11][12] Understanding the mechanistic basis for these and other similarly interesting fi ndings, 13 including a cognitive benefi t from nicotine, 2 would be of obvious importance. The name " neuronal " was based principally on the tissue source of the DNA libraries from which these receptors were fi rst cloned, the brain, 14 but growing evidence indicates that cells other than neurons throughout the body express these receptors 15 , 16 including lymphocytes, macrophages, dendritic cells, adipocytes, keratinocytes, endothelial cells, and epithelial cells of the intestine and lung.…”

Neuronal nicotinic receptors as novel targets for inflammation and neuroprotection: mechanistic considerations and clinical relevance

“…The potential for neuroprotection is supported by numerous in vitro studies demonstrating NNR-mediated protection of cells from a variety of toxic challenges, including brain injury [15] , oxygen-glucose deprivation [16][17][18] , oxidative stress [16] , β-amyloid toxicity (reviewed in [14] ), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) kainite and glutamate excitotoxicity [19][20][21] , ethanol exposure [22] , and nerve growth factor (NGF) deprivation [23][24][25][26] . Similarly, a number of studies using in vivo models have demonstrated neuroprotection by the reduction of β-amyloid expression in the APPsw mouse (a transgenic model of AD) [27] , surgically induced neuronal loss through nucleus basalis lesions [28] , chemically induced neurotoxicity mediated by MPTP toxicity and systemic kainic acid-induced excitotoxic effects (reviewed in [19,24] ), glutamate toxicity in the spastic HanWistar rat [29] , cerebral ischemia-reperfusion [30] , chronic ischemia models, and paraquat toxicity [31] .…”