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Parkinson's disease is the second well known neurodegenerative disorder after Alzheimer's disease that hampers the motor activity in an aged patient. Increasing evidences reveal the nicotine administration has convincing neuroprotective rather than neurorestorative effect in PD patients. PD is largely characterized by a decline in nAChRs (mainly dopamine related) and largely affected nicotinic cholinergic system. There occurs a decrease in nAChRs in both demented and non demented patients with PD. Stimulation of nAChRs located on pre-synaptic dopaminergic neurons by nicotine increases dopamine release in the striatum (Michele et al., 2000). Huang et al., 2010 used rat and monkey models where rats were pre- and post-administrated to nicotine unilaterally with 6-OHDA. Here nicotinic pre treatment attenuated behavioural defects and lessened lesion induced loss of striatal dopamine transfer. Chronic nicotine treatment differentially regulates striatal α6β2 nAChRs expression and function (McIntosh et al., 2010). Chronic nicotine treatment via drinking water largely increased the burst and non- burst endogenous dopamine release in the animal models. Studies have shown the effect of in vivo chronic exposure to nicotine on functioning of α4β2 nAChR in nigrostriatal dopaminergic (DA) pathway. Besides the role of nicotine in neurological disease treatment, it has also been seen that nicotine treatment in mice up regulates levels of RYR-2 thereby affecting an individual's cognitive and addictive properties (Ziviani et al., 2010). Through the nAChRs brain reward circuits, nicotine alters DA neuronal function in ventral tegmental area and increases dopamine release from VTA to nuclear accumbens that leads to nicotine reward, tolerance and dependence. Levodopa and L-DOPA induced therapy, where D1 and D2 dopamine receptors are largely targeted, are few other prescribed treatments for PD. Beside this, in present study, we focus on the beneficial effects of nicotine as a therapeutic target to minimize the risk of Parkinson's disease. However, exposure of nicotine is a major concern for PD therapy. Hence, it is important to know the biology behind the threshold of nicotine intake by a PD patient so that it does not exert any debilitating effect as a potential carcinogen.
The focal point of dissertation in this article is the selective pharmacological chaperoning of acetylcholine receptor number and subsequent modification of their stoichiometry (Lester et al.; 2009). It has been largely hypothesized that this protocol forms the fortitude of the classical observation that chronic and controlled exposure to nicotine induces the systematic activation of nicotinic acetylcholine receptors (nAChRs).The basic guideline driving this hypothesis is the gradual adaptation of nicotine receptors to chronic nicotine exposure. It is the malfunctioning of this chaperoning process that causes the catastrophic nicotine addiction. This mechanism may also chip in to the underlying fact of certain inadvertent therapeutic effects of tobacco use including the inverse correlation between the highly debated tobacco use and Parkinson's disease. There occur several identified as well as ongoing researches on the chemical and pharmacokinetic properties that render exogenous nicotine a more compelling pharmacological property than endogenous acetylcholine. One imperative hypothesis pinched from these studies implies that the therapeutic relevance of nicotinic receptor drugs should be studied at the intracellular level to achieve a thorough insight about its beneficence (Shalini, your effort is appreciable but at the same time you have to make your review more scientific by adding soem new references.
Parkinson's disease is a menacing neurodegenerative disorder largely characterized by extensive damage caused to the nigrostriatal dopaminergic system thereby impairing the motor activity of the patient. Several current therapies devised for this terminal disease impart only a symptomatic relief often coupled with grim side effects (Quik et al.; 2007). Thus there occurs a dire necessity for continuous search for a novel compound for the treatment of Parkinson's disease symptoms, as well as succumb the progression of the disease. Nicotine administration has largely proven to improve the motor movement associated challenges that arise as an upshot of the nigrostriatal damage in Parkinson's patients. Sizeable number of studies coupled with several other findings has largely drawn the conclusion that there occurs reduced incidence of Parkinson's disease in smokers mainly due to the occurrence of nicotine in tobacco. , These observations conclusively suggest that nicotine treatment may be beneficial in Parkinson's disease. Nicotine interacts with multiple nicotinic receptor (nAChR) subtypes in the peripheral and central nervous system, as well as in skeletal muscle. Large scale experiments conducted have assured that striatal α6β2 nAChRs are predominantly susceptible to the nigrostriatal damage characteristic to Parkinson's disease. Divergent to this observation, it was found that α4β2 nAChRs are decreased to a much minor extent under the same conditions of nigrostriatal damage. These annotations suggest that the development of nAChR agonists or antagonists mainly targeting α6β nAChRs may represent a particularly advantageous target for Parkinson's disease therapeutics (You have to explain this figure) .
Fig.1- Putative subunit composition of nAChR subtypes in rodent, monkey and human striatum. (Quick et al.; 2005) I hope you know Putative mean, if yes then you should include some fresh ideology if you read some papers)
Although for a substantial part, nicotine has been accredited as a pharmacologically vigorous chemical in tobacco, its occurrence in cigarette in consortia with numerous other carcinogenic substances accounts for its ailing reputation of being a major carcinogen in majority of cancer patients in India. There occurs a throbbing need to scientifically evaluate the complex pharmacological action of pure nicotine, using different routes of administration and, therefore shifting rates of absorption. Tobacco smoking produces several important behavioural and central nervous system effects. So a meticulous study pertaining the activity and biological mechanism of the other chemicals in tobacco should be done before wholly ruling out the prospect of nicotine usage as a pharmacologically active substance for treating Parkinson's disease.
There exists a noteworthy diversity of neurotransmitter compounds in the striatum, the pivotal brain region in the pathology of Parkinson's disease, movement disarray characterized by rigidity, tremor and bradykinesia (add some good references in entire review.Reference section is not appealing however your statements are worthy but strengthen your statements by adding some good references)..
Fig-2 Schematic representation of nAChR localization within the nigrostriatal pathway based on receptor binding, antibody immunoprecipitation and functional studies. The nigrostriatal dopaminergic terminals express three subtypes, the α4β2*, α6β2β3 and α6α4β2β3 nAChR populations (Quik M, O'Leary K, 2005) you should include this figure into the text as a part of inference.
The striatal dopaminergic system, which is particularly vulnerable to neurodegeneration in this disorder, appears to be the primary contributor to these motor problems. Nicotine predominantly, but not exclusively, stimulates nicotinic acetylcholine receptors (nAChRs) thus influencing several therapeutic functions relevant to Parkinson's disease mainly the upregulation of neurotransmitter. In accretion, recent development shows that nicotine reduces L-dopa-induced anomalous involuntary movements, a debilitating impediment of L-dopa therapy for Parkinson's disease. These pooled observations suggest that nAChR stimulation may represent a functional treatment strategy for Parkinson's disease to attain neuroprotection and symptomatic treatment. Prominently, only selective nAChR subtypes occur in the striatum including the α4β2, α6β2 and α7 nAChR populations. Treatment with nAChR ligands directed to these subtypes may thus cede optimal therapeutic benefit for Parkinson's disease, with a minimum of adverse side effects. So the foremost challenge that surrounds this hypothesis is why someone should resort to nicotine usage instead of using conventional commercial drugs to curb Parkinson's disease.
WHY TARGET nAChRs?
Nicotinic receptors, a lineage of ligand-gated ion channels that arbitrate the effects of the neurotransmitter acetylcholine, are among the best understood allosteric membrane proteins from a structural and functional perspective. A number of topical studies have established the potential for neuronal nicotinic acetylcholine receptor (NNR)-mediated neuroprotection and, more lately its anti-inflammatory effects. NNRs are heterogeneous in biological systems, moderately as an outcome of the genetic diversity of subunit-encoding genes. Nine of the sixteen human genes that encode the subunits comprising the pentameric structures are expressed exclusively in the human brain, with predominance, but not exclusive nature. Presynaptic nicotinic acetylcholine receptors (nAChRs) heterotypically modulate the release of non-cholinergic chemical messengers such as GABA, glutamate, serotonin, norepinephrine, dopamine (DA) growth factors, and various cytokines. The α4β2 and α7 NNR subtypes are the most copious nicotinic receptor subtypes in the mammalian brain. Both appear to play a governing role in cognitive processes such as learning and memory. Human α4β2 NNRs expressed in transfected cell lines, as well as those expressed in vivo, are present as a mixture of two stoichiometries, (α4)2(β2)3 and (α4)3(β2)2. The former displays high sensitivity (HS), while the latter exhibits low sensitivity (LS) to agonist activation. The calcium permeability and affinity for nicotine of these two stoichiometries have also been shown to vary. The LS subtype has a lower affinity for nicotine and acetylcholine and displays high calcium permeability. Conversely, the HS subtype has a greater affinity for nicotine and acetylcholine and exhibits lower calcium permeability. The α7 nAChr are expressed constitutively in the human body irrespective of health or disease condition. This nAChr subtype has been the focus of intense scrutiny in recent years, and it is becoming clear that it plays ubiquitous roles that range from cognitive processes to modulation of specific neurotransmitters and neuroprotection following various insults ranging from chemical toxicity to β-amyloid-induced cell death, normalization of sensory gating in schizophrenic patients and, more recently, as a central regulator of the inflammatory process. Similarly, a role for α4β2 in cognitive processes and neuroprotection has surfaced, suggesting either superfluous pathways within the same neurons or cell-specific expression of NNRs that regulate cell survival. Supplementary evidence, although limited, has professed a potential role for α6β2 in providing an aegis against nigrostriatal damage in mice. A number of studies conversely have demonstrated that α4β2 neuronal nicotinic receptors function independently of α7 to stimulate neuroprotection and contribute to neuronal survival in vivo. α6 nAChRs are selectively expressed in dopamine (DA) neurons and participate in cholinergic transmission. A great deal of evidence has been generated of mice with gain-of-function α6 nAChRs, which isolate and amplify cholinergic control of DA transmission.
SUBSTANTIAL PROOF SUPPORTING THE HYPOTHESIS:
Chronic intermittent administration of nicotine has also shown evidences of protection against MPTP toxicity, whereas chronic infusion of nicotine enhances MPTP toxicity. Nicotine, however, is always neuroprotective in primate models of MPTP toxicity. Chronic nicotine treatment administered via drinking water for several months before and during the toxic insult normalizes a number of parameters in the dopaminergic system. For instance, nicotine administration attenuates the loss of tyrosine hydroxylase (TH; an enzyme involved in DA synthesis), DA, DAT (a marker of dopaminergic terminals), VMAT (another marker of dopaminergic terminals), and NNRs as a result of MPTP toxicity. In addition, chronic nicotine administration in MPTP-treated primates normalizes nicotine-induced DA release, DA turnover, and synaptic plasticity. These data entail that nicotine promotes an augmentation in DA neuronal processes and reduces nigrostriatal damage. Thus, it appears that nicotine administration reduces DA deficits resulting from nigrostriatal damage and supports the development of NNR ligands as promising therapeutics for PD. There is considerable evidence for nicotinic neuroprotection in several in vivo models of PD.
Nicotine is neuroprotective against 6-OHDA lesions of the nigrostriatal tract only at low doses. Nicotine also appears to be more effective against partial, but not complete dopaminergic lesions and when administered both and after toxic insult. (Singh et al; 2008)
Fig-3 Preferential decline in the striatal α6α4β2β3 nAChR subtype in animal models (mouse and monkey) of nigrostriatal damage and Parkinson's disease. (Quik et al; 2007) In review you can not take the figures as such you have to mention why this figure is suitable for your text?
The α4β2 subunits of the nAChR, on which nicotine binds with its highest affinity, seem to be implicated in nicotine therapy. By employing the radioligand 2-[18F] F-A-85380 and positron emission tomography (PET) efforts were made on hypothesizing whether these receptors are altered in patients with PD. The preliminary data strongly suggested an amendment of α4β2 nAChRs availability in PD. While the regional decrease of the α4β2 nAChRs is in accord with post mortem studies in PD, the increased availability of the α4β2 nAChRs could represent denervation supersensitivity. Further investigation in a larger group of patients is underway. (Meyer et al, 2005)
A test involving the administration of nicotine to pregnant Rhesus monkeys from gestational day 30 through 160 by continuous infusion, attaining maternal plasma levels comparable to those in smokers (30ng/ml). Foetal brain regions and peripheral tissues were examined for nAChR subtypes, other neurotransmitter receptors, and indices of cell signalling and cell damage. Nicotine evoked nAChR upregulation, but with distinct regional disparities indicative of selective stimulatory responses. Later several attempts were made to compensate the adverse effects of nicotine with standard dietary supplements known to interact with nicotine. By itself, choline elicited nicotine-like actions commensurate with its promotion of cholinergic neurotransmission. When given in combination with nicotine, choline protected some regions from damage but worsened nicotine's effects in other regions. Correspondingly, Vitamin C supplementation had mixed effects, increasing nAChR responses while providing protection from cell damage in the caudate, the brain region most prone to oxidative stress. The inclusive results indicated that nicotine elicits neurodevelopment damage that is highly selective for different brain regions, and that dietary supplements can largely mask the adverse effect of nicotine therapy. (Slotkin et al; 2004)
Another study included numerous rodent models for chronic nicotine administration. These models include subcutaneously implanted mini osmotic pumps, nicotine-spiked drinking water, and self-administration via jugular cannulae. Administration of nicotine via these routes affects the immune system. Smokers frequently use nicotine patches to quit smoking, and the immunological effects of nicotine patches are largely unknown. To determine whether the nicotine patch affects the immune system, nicotine patches were affixed daily onto the backs of Lewis rats for 3 to 4 weeks. The patches efficiently raised the levels of nicotine and cotinine, a nicotine metabolite, in serum and strongly inhibited the antibody-forming cell response of spleen cells to sheep red blood cells. Moreover, immunosuppression was associated with chronic activation of protein tyrosine kinase and phospholipase C activities. Thus, in these animal models of nicotine administration, the nicotine patch efficiently raises the levels of nicotine and cotinine in serum and impairs both the immune and inflammatory responses. (Kalra et al; 2004)
L-dopa therapy for Parkinson's disease leads to dyskinesias or abnormal involuntary movement (AIMs) for which there are few treatment options. Researches and previous data showed that nicotine administration reduced L-dopa-induced AIMs in parkinsonian monkeys and rats. To further understand how nicotine mediates its antidyskinetic action, major investigation on the effect of nicotinic receptor (nAChR) agonists in unilateral 6-OHDA-lesioned rats with varying striatal damage were studied. Vigorous initial tests ensued the administration of the drugs in L-dopa-treated rats with a near-complete striatal dopamine lesion (>99%), the standard rodent dyskinesia model. Varenicline, an agonist that interacts with multiple nAChRs, failed significantly to reduce L-dopa-induced AIMs, while 5-iodo-A-85380 (A-85380), which acts selectively at α4β2 and α6β2 subtypes, reduced AIMs by 20%. By contrast, both Varenicline and A-85380 reduced L-dopa-induced AIMs by 40-50% in rats with a partial striatal dopamine lesion. Neither of the drugs worsened the antiparkinsonian action of L-dopa. The results stated that selective nicotinic agonists reduce dyskinesias, and that they are optimally effective in animals with partial striatal dopamine damage. These findings suggest that presynaptic dopamine terminal α4β2 and α6β2 nAChRs are critical for nicotine's antidyskinetic action. The current data have important implications for the usage of nicotinic receptor-directed drugs for L-dopa-induced dyskinesias, an incapacitating motor complication of dopamine replacement therapy for Parkinson's disease (Carroll et al; 2011)
The ubiquitin-proteasome system tags and removes unwanted, misfolded, or damaged proteins from cells as well as regulates nicotinic receptor levels. The ubiquitin-proteasome system has shown phenomenon based implication in Parkinson's disease, with aberrant activity identified in both sporadic and familial forms of the disease. The involvement of the ubiquitin-proteasome system in nicotinic receptor regulation and Parkinson's disease pathology suggests a link between the two, which forms the basis of the present hypothesis. Specifically, the hypothesis considers that smoking reduces the risk of Parkinson's disease through the upregulation of nicotinic cholinergic receptors in key brain regions involved in Parkinson's disease. The upregulation of these receptors is hypothesized to increase the activity of the ubiquitin-proteasome system, which is believed to prevent neurodegeneration caused by the accumulation and subsequent aggravation of misfolded or damaged proteins or other consequences of inadequate protein sequestration or degradation. This hypothesis is supported by evidence documenting the upregulation of nicotinic receptors in the brains of smokers, neuroprotective effects of nicotine, reduced activity of the ubiquitin-proteasome in Parkinson's disease, and increased activity of the ubiquitin-proteasome system in animals exposed to chronic nicotine. Additional research is needed to test several predictions of the hypothesis, including increased activity of the ubiquitin-proteasome system in key brain regions of smokers.
1. Six patients with advanced idiopathic PD received increasing daily doses of transdermal nicotine up to 105 mg/day over 17 weeks. All patients but one accepted the target dose. Nausea and vomiting were frequent but moderate, and occurred in most of the patients (four of six) who received over 90 mg/day and 14 weeks of nicotine treatment. During the plateau phase, patients enhanced their motor scores and dopaminergic treatment was reduced. These results confirm the feasibility of chronic high dose nicotinic treatment in PD but warrant validation of the beneficial effects by a randomized controlled trial. (Villafane et al; 2007)
2. Two groups of mice were chronically exposed to cigarette smoke (a low exposure subgroup and a high exposure subgroup; 5 exposures per day at 2-h intervals), two other groups received nicotine treatment (two doses tested 0.2 and 2 mg/kg, 5 injections per day at 2-h intervals) and one group placebo. On day 8 after the beginning of the treatment, 4 injections of MPTP hydrochloride (15 mg/kg, at 2-h intervals) or saline were administered to these animals. Nicotine and cotinine plasmatic concentration was quantified by the HPLC method, and degeneration of the nigrostriatal system was assessed by tyrosine hydroxylase (TH) immunohistochemistry. The loss of dopaminergic neurons induced by MPTP in the substantia nigra was significantly less severe in the chronic nicotine treatment groups (at 0.2 and 2 mg/kg) and the low exposure to cigarette smoke group than in the high exposure to cigarette smoke subgroup and the placebo treated subgroup. In contrast, no preservation of TH immunostaining of nerve terminals was observed in the striatum in any group. This suggests that nicotine and low exposure to cigarette smoke may have a neuroprotective effect on the dopaminergic nigrostriatal system by an as yet unknown mechanism (Parain et al; 2003)
Epidemiological studies have largely indicated that smoking is a negative risk factor for Parkinson's disease (PD). The purpose of this study was to assess the interplay of the nicotinic factors and the specific neuronal receptors that govern the nigrostriatal damage during Parkinson's disease. To approach this, several rodent models along with innumerous clinical trials were efficiently undertaken to systematically evaluate the neuroprotective function of nicotine.
While it has long been documented that nicotine contained in tobacco leaves gives rise to major public health problems, through these studies a genuine attempt has been made to prove that this alkaloid can have beneficial effects too. However, it is only with the identification of a family of genes coding for the neuronal nicotinic acetylcholine receptors and increased knowledge of their expression and function in the central nervous system that these receptors have received attention concerning their potential as drug targets. In light of the latest findings about nicotinic acetylcholine receptors and their involvement in disease states it has been possible to review the design of new drugs targeted to these ligand-gated channels. Beneficial and possible undesirable actions of agonists, antagonists and allosteric modulators are discussed and placed in perspective of our most recent knowledge.
Through a wide spectrum of results it had been depicted that nicotine patches fail to render any kind of therapeutic effect to a Parkinson's patient. So the focus now shifts to the application of nicotine gum usage to render some therapy. To prove this a study was done to assess the therapeutic effects of nicotine chewing gum in patients with early-onset Parkinsonism (EOP). The subjects were 8 patients with early-onset Parkinsonism (male/female = 4/4, mean age; 51.3 years). Four out of 8 patients had a history of smoking (smokers). To estimate the effects of nicotine gum, the scores on the Unified Parkinson's Disease Rating Scale (UPDRS) and auditory event-related potentials (ERPs) were studied before and after taking nicotine gum in the EOP patients. In smokers, UPDRS scores improved by more than 10% and the P300 latency of auditory ERPs were shortened by more than 30 msec. In contrast, nicotine had no remarkable effects on UPDRS scores or auditory ERPs in non-smokers. (Mitsuoka et al. , 2009)
Through this it can be largely professed that nicotine chewing gum may be a potential choice for the treatment of EOP patients, especially when they have a history of smoking. (Make this figure in powerpoint, transfer this to Adobe and then save s tiff file for 300 dpi then save after that import this file into your text.
Via drinking water
L DOPA THERAPY
NNR MEDIATED THERAPY
ANOMALOUS INVOLUNTARY MOVEMENT
REDUCED MPTP TOXICITY
REDUCED 6-OHDA LESIONS
α 6 β 2
α 4 β 2
Causes dopamine release from VTA to nuclear accumbens increasing nicotine reward, tolerance and dependence.
Increases RYR-2 production thereby enhancing cognitive and addictive properties.