Pravir Kumar et al. / Journal of Pharmacy Research 2011,4(10),3514-3519
Review Article ISSN: 0974-6943
Available online through www.jpronline.info
Nicotine therapy: whether a good or bad move in Parkinsonism in concert with HSPs? Pravir Kumar1, 3, *, Shalini Pal 1, R. Karunya 1 and Rashmi Ambasta 2 Functional genomics laboratory, Center for Biomedical Research, Vellore Institute of Technology, Vellore, TN 632014 (INDIA) 2 Cancer biology laboratory, Center for Biomedical Research, Vellore Institute of Technology, Vellore, TN 632014 (INDIA) 3 Department of Neurology, Adjunct faculty, Tufts University School of Medicine, Boston, MA (USA)
1
Received on: 19-06-2011; Revised on: 08-07-2011; Accepted on:01-10-2011 ABSTRACT Parkinson’s disease (PD), the second most prevalent neurodegenerative disorder, impairs the motor activities in patient. Increasing evidences reveal the nicotine administration has neuroprotective rather than neurorestorative effect in PD. PD is largely characterized by a decline in nicotinic acetylcholine receptors (nAChRs) and affected nicotinic cholinergic system. Stimulation of nAChRs located on pre-synaptic dopaminergic neurons by nicotine increases dopamine release in the striatum. Rat and monkey models were used where rats were pre- and post-administered with nicotine and 6-OHDA [31]. Here nicotinic pre treatment attenuated the behavioral defects and lesion induced loss of striatal dopamine transfer. However, chronic nicotine treatment differentially regulates striatal nAChRs expression and function [59]. Chronic nicotine treatment via drinking water increased the burst and non- burst endogenous dopamine release in the animal models. Moreover, nicotine administration in mice up regulates levels of Rynodine receptor-2 (RyR-2) thereby affecting an individual’s cognitive and addictive properties [89]. Growing awareness in the field of molecular chaperones can be an additive value to treat the PD in association with nicotine. However, little is known about the effect of nicotine on heat shock proteins (HSPs) under stressed condition. In this review, we focus on the beneficial effects of nicotine as a therapeutic molecule to minimize the risk of PD. Conversely, exposure of nicotine is a major concern for PD therapy hence, it is necessary to understand 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.
Key words: Parkinson’s disease, Nicotinic acetylcholine receptors, Heat Shock Proteins; Neuronal nicotinic acetylcholine receptor, Nicotine therapy INTRODUCTION: The central theme of this review is to highlight the selective pharmacological chaperoning of acetylcholine receptor number and subsequent modification of their stoichiometry [85]. This protocol forms the fortitude of the observation that chronic and controlled exposure to nicotine induces the systematic activation of nicotinic acetylcholine receptors (nAChRs) [48]. The basic guideline derived from this hypothesis is the gradual adaptation of nicotine receptors upon chronic nicotine exposure. However, any malfunctioning of this chaperoning process results in nicotine addiction [10]. This mechanism may also chip into the underlying fact of certain inadvertent therapeutic effects of tobacco intake including the inverse correlation between the highly debated tobacco use and PD [56]. There are 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. An essential theory derived from these studies indicates the therapeutic relevance of nicotinic receptor drugs should be studied at the intracellular level to achieve a thorough insight about its mechanism [59]. PD is a menacing neurodegenerative disorder largely characterized by extensive damage caused in the nigrostriatal dopaminergic system thereby impairing the motor activity in patient. Current therapies devised for this terminal disease impart only a symptomatic relief often coupled with grim side effects [59, 64].Thus a dire necessity for continuous search of novel compounds to treat the PD 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 [52, 24]. Sizeable number of studies coupled with several other findings has largely drawn the conclusion that there is a reduced incidence of PD in smokers mainly due to the occurrence of nicotine in tobacco. These observations conclusively suggest that nicotine treatment may be beneficial in PD; however the detrimental side effect of other compounds present in tobacco smoking cannot be ignored. Nicotine interacts with multiple nicotinic receptor (nAChR) subtypes in the peripheral and central nervous system, as well as in skeletal muscle [62]. Large scale experiments concluded that striatal α6ß2 nAChRs are predominantly susceptible to the nigrostriatal damage that is a hallmark feature in PD [39]. On contrary, it has been found that α4ß2 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 α6ß nAChRs that might represent a particularly advantageous target for PD therapeutics [86]. Nicotine administration has been reported to improve motor deficits that arise with nigrostriatal damage in PD and several nAChR populations have been identified in the nigrostriatal system. These include α4ß2 and α6ß2ß3 subtypes that are decreased primarily with severe nigrostriatal degeneration, and the α6α4ß2ß3 subtype that is significantly reduced even with only moderate damage. Several findings suggest that the α6α4ß2ß3 nAChR subtype represents a marker for neurons particularly vulnerable to nigrostriatal damage [12]. Although for a substantial part, nicotine has been accredited as a pharmacologically deleterious component in tobacco and its occurrence in cigarette in consortia with numerous other carcinogenic substances accounts for its ailing reputation to provoke the cancer [8]. Therefore it is necessary to evaluate the complex pharmacological actions of pure nicotine, its usage, different routes of administration and finally the rate of absorption. Tobacco smoking produces several behavioral and central nervous system defects hence a meticulous study pertaining to the activity and biological action of the other chemicals present in tobacco should be studied extensively [10]. This will enable us to understand the efficacy of nicotine usage as a pharmacologically active substance to treat the PD (PD) [7].
Parkinson’s Disease
*Corresponding author. Dr. Pravir Kumar, PhD Assistant Director and Associate Professor, 206-Center for Biomedical Research, SBST, VIT University, Vellore, TamilNadu 632014, INDIA. Adjunct Faculty, Tufts University School of Medicine, Boston, MA (USA). E-mail:
[email protected];
[email protected] Phone: +91-416-220-2592; +91-9003386752
Impaired motor activity
Decline in nAChRs
Damage to nigrostraital system
Inhibition of Complex 1 (ETC) in MPTP induced PD
Figure 1.Progression of Parkinsonism indicating an impaired motor activity, decreased neurotransmitter receptors and disturbance in nigrostraital system along with electron transport system.
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Pravir Kumar et al. / Journal of Pharmacy Research 2011,4(10),3514-3519 There are several neurotransmitter compounds exist in the striatum, which are important component in the pathology of PD, for instance movement disarray, rigidity, tremor and bradykinesia. The striatal dopaminergic system, which is particularly vulnerable to neurodegeneration (Fig.1), appears to be the primary contributor to these motor problems [48, 49] Nicotine predominantly, but not exclusively, stimulates nicotinic acetylcholine receptors (nAChRs) thus influencing several therapeutic functions relevant to PD mainly the upregulation of innumerous neurotransmitter. In accretion, recent development shows that nicotine reduces L-dopa-induced anomalous involuntary movements, a debilitating impediment of L-dopa therapy for PD [31]. Above observations suggest that nAChR stimulation may represent a functional treatment strategy for PD to attain neuroprotection and symptomatic treatment. Prominently, only selective nAChR subtypes occur in the striatum including the α4ß2, α6ß2 and α7 nAChR populations. Treatment employing nAChR ligands directed to these subtypes may thus cede optimal therapeutic benefit for PD, with a minimum of adverse side effects [4, 30]. So the foremost challenge that surrounds this hypothesis is why someone should resort to nicotine usage instead of using conventional commercial drugs to curb PD.
Neuronal nicotine acetylcholine receptors
Selective pharmacological chaperoning of nAChR number and subsequent modification of their stoichiometry
Chronic and controlled exposure to nicotine that induces the systematic activation of nAChRs Modulate activity of GABA, glutamate, serotonin, nor epinephrine, dopamine (DA growth factors)
Nicotine administration improves motor movement in patients of PD Figure 2: Nicotine mediated therapy in Parkinson’s disease enhances the restoration of motor activities by modulating several neurotransmitters. 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 [5, 81]. A number of topical studies have established the potential for neuronal nicotinic acetylcholine receptor (NNR)-mediated neuroprotection and, more lately its anti-inflammatory effects [9] 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 nAChRs heterotypically
modulate the release of non-cholinergic chemical messengers such as GABA, glutamate, serotonin, norepinephrine, dopamine (DA) growth factors, and various cytokines (Fig. 2). The α4ß2 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 cognition and memory [37]. Human α4ß2 NNRs expressed in transfected cell lines, as well as those expressed in vivo, are present as a mixture of two primary stoichiomet ries, (a4)2(ß2)3 and (α4)3(ß2)2 [85]. 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 [75]. 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 ßamyloid-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 α4ß2 in cognitive processes and neuroprotection has surfaced, suggesting either superfluous pathways within the same neurons or cellspecific expression of NNRs that regulate cell survival [51]. Supplementary evidence, although limited, has professed a potential role for α6ß2 in providing an aegis against nigrostriatal damage in mice. A number of studies conversely have demonstrated that α4ß2 neuronal nicotinic receptors function independently of α7 to stimulate neuroprotection and contribute to neuronal survival in vivo. The a6 nAChRs are selectively expressed in dopamine (DA) neurons and particip ate in cholinergic transmission [22, 69]. A great deal of evidence has been generated of mice with gain-of-function in α6 nAChRs that isolate and amplify cholinergic control of DA transmission [86]. Studies have shown the effect of in vivo chronic exposure to nicotine on functioning of α4ß2 nAChR in nigrostriatal dopaminergic (DA) pathway. SUBSTANTIAL PROOF SUPPORTING THE nAChR HYPOTHESIS: Chronic intermittent administration of nicotine has also shown evidences of protection against MPTP toxicity, whereas chronic infusion of nicotine enhances MPTP toxicity [23]. Nicotine, however, is always neuroprotective in primate models of MPTP toxicity [40]. 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 several known markers that are involved in the progression of PD such as tyrosine hydroxylase (TH): an enzyme involved in DA synthesis, Dopamine transporter (DAT): primary marker of dopaminergic terminals, Vesicular monoamine transporter (VMAT): secondary 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, its turnover, and synaptic plasticity [23, 71, 19, 20]. These data entail that nicotine promotes an augmentation in DA neuronal processes and reduces nigrostriatal damage [34] 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 [9]. Nicotine is neuroprotective against 6-OHDA lesions of the nigrostriatal tract only at low controlled doses [17, 26, 1]. Nicotine also appears to be more effective against partial, but not complete dopaminergic lesions and when administered both and after toxic insult. [77]. The α4ß2 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 PD patients [25, 36, 38]. The preliminary data strongly suggested an amendment of α4ß2 nAChRs availability in PD. While the regional decrease of the α4ß2 nAChRs is in accord with post mortem studies in PD, the increased availability of the α4ß2 nAChRs could represent the denervation supersensitivity [51]. Further clinical investigation in a larger group of patients is underway.
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Other approach to remove the waste protein from the cell system is mediated through Ubiquitin-proteasome system tags that eliminates unwanted, misfolded, or damaged proteins from cells as well as regulates nicotinic receptor levels. The ubiquitin-proteasome system has shown phenomenon based implication
The heat shock response is observed in case of stress conditions and is mediated via the HSPs [43] Many of the HSPs have important cellular functions that is not related to stress alone. Of exacting notice is their utility in unfolding, sorting and degrading other proteins. It largely suggests that the HSP may be implicated in helping the cell to stabilize existing proteins or purge unwanted or damaged proteins. Post stress, the elevation in the level of HSPs mainly reflect the necessity to eliminate newly damaged proteins. Recent studies have examined the ability of nicotine to act as a stress inducer. These findings were positive only for extremely high doses of nicotine, for lower doses the results were found to be negative. Thus it was hypoth-
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[45]
[28], [79] [88] [27]
References [53] ,[14]
Hsp 90 binds to Hsp 70 thereby influencing the clustering of mAchRs by Tid1.
Level is upregulated under stress condition induced by Nicotine and/or ethanol Interaction of Hsp 90 with Rapsyn causes upregulation of surface AChRs.
Hsp 90
Hsp 28
Hsp 40
Hsp 40 protein family member Tid1(tumorous imaginal discs) influence the aggregation of AchRs in adult muscle fibres.
GRP 78 Activates signalling cascade and elevates l evels of calcium Together with Hsp70 modulate the posttranscriptional changes in neurons.
Muscle acetylcholine receptors (mAchRs)
Heat shock proteins (HSPs) are a conserved family of proteins whose expression increases in response to a variety of different metabolic insults. One well studied response to sudden adverse environmental changes is the heat shock or stress response. Besides rendering protective properties to the cell, HSPs have been associated with several other molecular functions. The realization that many of the HSPs function as “molecular chaperones” helps explain why these proteins are so critical for normal growth, as well as the ability of the cell to survive different metabolic insults. Hsp90 interacts with a variety of protein kinases and transcription factors important for growth and development. Hsp60 families have long been associated with immunogenic proteins under conditions that are unfavourable for protein folding. Hsp70 family, function as a type of “molecular crowbar or detergent” to facilitate the disassembly of large protein complexes needed to initiate the early stages of DNA replication.In addition there also occur Hsp 110 and Hsp 40 that act as co factors for several Hsp 70 chaperones.
NICOTINE AND HSPS- WILL HEAT SHOCK PROTEINS HAVE ADDITIVE ROLE IN NICOTINE MEDIATED THERAPY IN PD?
Acetylcholine receptor (AChR)
ACETYLCHOLINE RECEPTORS AND HEAT SHOCK PROTEINS
Rapsyn, an acetylcholine receptor (AChR)-interacting protein, is essential for synapse formation at the neuromuscular junction (NMJ). It was largely identified that heat shock protein 90ß (Hsp90ß) acts as a component of surface AChR clusters [46] The Hsp90ß-AChR interaction required inhibition of Hsp90ß activity or expression, or disruption of its interaction with rapsyn -induced formation of AChR clusters. It was also hypothesized that Hsp90ß is necessary for rapsyn stabilization thereby synchronized its proteasome-dependent degradation. Together, these results indicate a role of Hsp90b in NMJ development by regulating rapsyn turnover and subsequent AChR cluster formation and maintenance. [88].
Hsp 70 Candidate receptor on APC; antitumor immune property Antibodies against Hsp 70 antigen in the sera of patients with MG largely target these receptors impairing motor activity Hsp 70 acts as a cochaperone for Tid1 thereby affecting the clustering of mAchRs.
L-dopa therapy for PD leads to dyskinesias or abnormal involuntary movement (AIMs) for which there are few treatment options [31] Researches and previous data revealed 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.[74] Vigorous initial tests ensued the administration of the drugs in L-dopa-treated rats with a near-complete st riatal dopamine lesion (>99%). Varenicline, an agonist that interacts with multiple nAChRs, failed significantly to reduce L-dopa-induced AIMs, while 5iodo-A-85380 (A-85380), which acts selectively at α4ß2 and α 6ß2 subtypes, reduced AIMs by 20%.[63] 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 these drugs worsened the antiparkinsonian fatal action of Ldopa which 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 α4ß2 and α6ß2 nAChRs are critical for nicotine’s antidyskinetic activity. 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 PD [31].
Hsp60, like many other heat shock proteins, is a molecular chaperone and plays an essential role in maintaining cell homeostasis under normal conditions. When patients with Myasthenia gravis, a grave autoimmune disorder, were studied, structural correlation was observed between Hsp60 and AchRs. The antibodies, occurring in an MG patient, cross-react with the infected individual’s Hsp60 and with any other molecule (e.g., AchRs) that shares epitopes with the Hsp60. The consequences of these cross reactions may vary depending on the human molecule involved, Hsp60 or AChR, but it is likely that pathological autoimmune processes will develop if the infection and the fabrication of auto antibodies persist [6].
Receptors ?2 macroglobulin signalling receptor (a2M*)
Another study included numerous rodent models for chronic nicotine administration. These models included subcutaneously implanted mini osmotic pumps, nicotine-spiked drinking water, and self-administration via jugular cannulae. Administration of nicotine via these routes affected the immune system. Smokers frequently use nicotine patches to quit smoking whose immunological effects is remains unsettled. 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 [35].
in PD, with aberrant activity identified in both sporadic as well as familial forms of the disease. The involvement of the ubiquitin-proteasome system in nicotinic receptor regulation and PD pathology suggests a link between the two, which forms the basis of the present hypothesis [72]. Specifically, the hypothesis considers that smoking reduces the risk of PD through the upregulation of nicotinic cholinergic receptors in key brain regions involved in the occurrence of PD. 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.
Table 1. Possible involvement of molecular chaperones in nicotine mediated therapy in Parkinson’s disease.
A test involving the administration of nicotine to pregnant Rhesus monkeys from gestational day 30 th till 160 th days 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 signaling 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 region which has high incidence of oxidative stress. These 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 [80].
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Pravir Kumar et al. / Journal of Pharmacy Research 2011,4(10),3514-3519 esized that nicotine, while perhaps by itself unable to instigate a stress response, might be able to augment the response induced by ethanol or heat shock [83]. The effect of nicotine was found to be profound in case of Hsp70 and Hsp 28 [27]. Careful examination suggested that the effect of nicotine is synergistic with respect to induction of HSP as well as thermotolerance and induction of specific HSF binding to HSE. This consequence was found to be exclusive in case of nicotine. The co induction of Hsp70 and Hsp28 by nicotine correlates with the increase in thermotolerance in the treated cells ( Table. 1). The induction of Hsp70 and Hsp28 or improved constitutive levels of one or both of these proteins has been proposed as important for the abdication of thermotolerance and thermal resistance in cells [27]. 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 PD, 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 [15]. THERAPEUTIC APPROACH The therapeutic approach towards PD could largely encompass the activity of HSP as well as the ubiquitin proteasome system. As already discussed, nicotine Table 2. Nicotine administration ameliorates and restore the motor activities in Parkinson’s disease. Subject considered
Treatment offered
6 patients suffering Increasing daily doses of from advanced idiopathic transdermal nicotine up to PD condition 105mg/day over 17 weeks.
Animal model (two groups of mice)
Observations
During the plateau phase of the trial, patients showed great enhancement in their motor activities and dopaminergic treatment was reduced. Nicotine Chewing Gum Nicotine had no remarkable effects on UPDRS on patients with EOP scores or auditory ERPs in non-smokers. However in case of patients with history of smoking, nicotine showed 10% increase in the levels. Chronically and periodically Quantitative estimation of nicotine and cotinine exposed to cigarette smoke level in plasma via HPLC suggested that low along with four exposure to cigarette smoke may have a injections MPTP hydrochloride. neuroprotective effect on the dopaminergic nigrostriatal system.
induces an upregulation of nAChRs as well as certain classes of HSP thereby rendering the property of thermotolerance to the cell. Additionally ubiquitin proteasome system has also been proved to have some therapeutic properties. It was shown that the a7 nAChR subunit is a target of the UPS, point to a prominent role of the proteasome in nAChR trafficking. Thus HSP and ubiquitin proteasome pathway can play a substantial role in rendering symptomatic relief to the patient with PD. For the beneficial effect of Nicotine, six patients were taken for study, suffering from advanced idiopathic PD condition received increasing daily doses of transdermal nicotine up to 105 mg/day over 17 weeks. One of these patients was taken as a control and received no dosage at all. Nausea and vomiting were frequent but moderate, and occurred in most of the patients who received over 90 mg/day and 14 weeks of nicotine treatment. During the plateau phase of the trial, patients showed great enhancement in their motor activities and dopaminergic treatment was reduced. These results confirmed the practicability of chronic high dose nicotinic treatment in PD but warranted the validation of the beneficial effects by a randomized controlled trial. [82] On animal model two distinct groups of mice were chronically and periodically exposed to cigarette smoke. One group with a low level of exposure and another being a high exposure subgroup with a dosage of 5 exposures per day at 2 hour intervals. Two other groups received, instead of the smoke, direct nicotine treatment (two doses tested 0.2 and 2 mg/kg, 5 injections per day at 2-h intervals) and one group was taken as placebo. On day 8 after the beginning of the treatment, four injections of MPTP hydrochloride (15 mg/kg, at 2-h intervals) were administered in all of these animals. Nicotine and cotinine concentration in the plasma were quantified by 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. This suggests that nicotine and low exposure to cigarette smoke may have a neuroprotective effect on the dopaminergic nigrostriatal system. [58]
Figure.3 Plausible therapeutic approach of nicotine administra tion in Parkinson’s disease (encompasses the activity of nicotine via various receptors to render the symptomatic releif in Parkinson’s disease patients
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Pravir Kumar et al. / Journal of Pharmacy Research 2011,4(10),3514-3519 CONCLUDING REMARKS Epidemiological studies have largely indicated that smoking has a negative risk factor for PD (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 PD (Fig. 3). To approach this, several rodent models along with innumerous clinical trials were efficiently undertaken to systematically evaluate the neuroprotective function of nicotine [76].
12.
13.
14.
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 [30]. 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 the most recent knowledge [81]. FUTURE PERSPECTIVE OF NICOTINE THERAPIES IN PD PATEINTS Through a wide spectrum of results it has been depicted that nicotine patches fail to render any kind of therapeutic effect in a Parkinson’s patient. Therefore, the focus now shifts to the application of nicotine gum usage to render a plausible therapy. To support these, clinical trials were conducted to assess the therapeutic efficacy of nicotine chewing gum in patients with early-onset of Parkinsonism (EOP). Initially, the focus was on a group of eight patients with early-onset of Parkinsonism (male/female = 4/4, mean age; 51.3 years). Four of these patients had a history of smoking. To estimate the ameliorating effect of nicotine gum on these patients, the scores on the Unified PD Rating Scale (UPDRS) and Auditory event-Related Potentials (ERPs) were studied before and after taking nicotine gum in the EOP patients. In the patients with the history of smoking, UPDRS scores showed an elevation of more than 10% and the P300 latency of auditory ERPs were decreased by more than 30 msec. Contrary to this; nicotine had no remarkable effects on UPDRS scores or auditory ERPs in non-smokers. [54] 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.
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Journal of Pharmacy Research Vol.4.Issue 10. October 2011
3514-3519
