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Nicotine Information Summary

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A number of compounds were identified as candidates for further study by the Committee to Identify Neuroprotective Agents in Parkinson's (CINAPS). Of these compounds, Minocycline, Creatine , CoQ10 and GPI 1485 have been selected for testing in the Neuroprotection Clinical Trial.

NICOTINE

The relationship between smoking and Parkinson's disease is not clear. Smokers have a lower rate of Parkinson's disease - about 50 percent less - than nonsmokers. In the brain, nicotine binds to nicotinic acetylcholine receptors. This binding starts a process that ends with the release of the neurotransmitter dopamine. Parkinson's disease patients have fewer of these receptors in their brains than healthy people. So the normal brain chemical that sets off the dopamine cascade cannot do its job. Drugs - like nicotine - that stimulate the receptors might increase the levels of dopamine in the brains of sufferers.

 

Scientific Rationale

  • A consistent, negative association between smoking and the incidence of PD has been shown in epidemiological studies
  • neuronal nicotinic cholinoceptors modulate Ach release and inc DA release
  • nicotine may reduce DA turnover, therefore decrease oxidative stress
  • intermittent (-) nicotine increases trophic factors in the brain (BFGF) some in vitro evidence of antioxidant effect

1. Morens, Neurology 1995; 45:1041-1051
2. Balfour, Pharmacol Ther 1996;72:51-81
3. Belluardo; Neuroscience 1998; 83:723-740
4. Linert, Biochimica et Biophysica 1999; 1454: 143-145

Animal Model Data

RODENT:

Mouse: Nicotine administered for 4 weeks with MPTP (4 inj/24 h) given on day 8, protected by 15% the reduction of DA neurons on the substantia nigra.

Rat: Chronic admin (1 mg/kg) sq nicotine, given 4 h before and 20,44 and 68 h after 6-OH DA prevented DA neuronal loss in the striatum, but not the substantia nigra. Other regimens (just before or just after lesion, were not effective). The beneficial effect of the nicotine was blocked by nAChR antagonist.

Mouse: Chronic (-) nicotine, by minipump, started the day before MPTP and cont'd for 2 weeks, resulted in a dose-dependant INCREASE in DA depletion. However, when (-) nicotine was given 4 times at 15 minute intervals, starting 10 min before MPTP REDUCED the DA depletion in the striatum and the SN. Other data is negative

1. Parain, Brain Res 2001;890:347-350
2. Costa, Brain Res 2001;888:336-3442
3. Janson, Clin Invest 1992;70:232-238
4. Sershen, Neurosci Lett 1988;93:270-274
5. Fung, Gen Pharmacol 1991;22:669-172

Pharmacokinetics (including blood brain barrier (BBB) penetration)

Rapidly enters the brain after various routes

1. Ghosheh, Drug Metab Disp 2001;29:645-651

Safety/Tolerability in Humans

Non-smoking ulcerative colitis patients treated with high doses of transdermal nicotine did not experience dependence or withdrawal 32 non-smoking PD patients were entered into a randomized, DB, placebo-controlled, 12 week trial of the efficacy and tolerability of transdermal nicotine patches (17.5 mg and 35 mg wks 2 and 3). No motor benefits were seen. 75% of patients reported minor side effects but they were similar between placebo and nicotine. No one discontinued due to side effects.

Transdermal nicotine can cause:

  • 47% local irritation
  • 3-9% diarrhea, dyspepsia, myalgia, abnormal dreams
  • 23% insomnia

1Pullan, NEJM 1994; 330:811-815
2Vieregge Neurology 2001;57
3MD Consult, nicotine monograph, 2002

Drug Interaction Potential

Not known to induce hepatic enzymes. Effects of cigarette smoking on CYP enzymes thought to be due to other components of smoke.

Clinical Trial/Epidemiological Evidence in Human PD

  • Extensive evidence of a negative association of smoking and PD (approximately 50% RR reduction) in multiple epidemiological studies with differing designs
  • Dose-effect relationship demonstrated with amount smoked and PD risk (case-control study)
  • Transdermal (16 patients) and chewing gum nicotine, in short-term studies did not improve (and sometimes worsened) motor symptoms in PD patients.
  • (Case series evidence of improvement with patch/gum combination)no long term studies

1. Morens Neurology 1995;45:1041-1051 (review of 35 studies)
2. Gorrell, Neurology 1999; 52: 115-119
3. Edersbach, Movement Disorders 1999;14:1011-1013
4. Clemens, Psychopharm 1995;41:168-174 (unable to obtain ref.)
5. Balfour, Pharmacol Ther 1996;72:51-81

Last updated July 01, 2008