BRAIN BITES

BY DR WAEL MY MOHAMED

Dr Wael MY Mohamed is with the Department of Basic Medical Science , Kulliyyah of Medicine , International Islamic University Malaysia ( IIUM ).

As Mark Twain famously quipped , “ Too much of anything is bad , but too much good whiskey is barely enough .” Perhaps the same logic applies to nicotine - where just the right amount might have unexpected benefits . Or , as Twain also joked , “ Quitting smoking is easy . I ’ ve done it thousands of times .” - a paradox that mirrors the surprising link between smoking and Parkinson ’ s risk !

INTRODUCTION

Numerous epidemiological studies have consistently shown a reduced frequency of Parkinson ’ s disease among smokers , prompting fascinating enquiries into the possible neuroprotective properties of tobacco smoke constituents .

Nonetheless , the processes that underpin this relationship are little understood , and whether smoking itself provides protection or whether other explanations account for this phenomenon continues to be a subject of contention .

Epidemiological Data . Numerous extensive cohort and case-control studies have shown that smokers have a reduced risk of getting Parkinson ’ s disease compared to non-smokers .

A meta-analysis of epidemiological data indicates that both present and past smokers demonstrate a decreased incidence of Parkinson ’ s disease , with a dose-dependent relationship showing that increased smoking intensity and duration correlate with a lower risk .

This inverse association has prompted researchers to hypothesise that specific components of tobacco smoke may possess neuroprotective properties , possibly postponing the development or mitigating the severity of Parkinson ’ s disease pathology .

SMOKING AND PD

Epidemiological studies have strangely associated cigarette smoking with a decreased incidence of Parkinson ’ s disease ( PD ), but the underlying processes are not well understood .

Considering that carbon monoxide ( CO ) levels are consistently but slightly higher in smokers , we hypothesised that CO may have a role in neuroprotection in Parkinson ’ s disease ( PD ).

Employing mouse models of Parkinson ’ s disease distinguished by α-synuclein buildup and oxidative stress , researchers show that low-dose carbon monoxide alleviates neurodegeneration and diminishes α-synuclein pathology .

The oral injection of carbon monoxide activates signalling cascades controlled by heme oxygenase-1 ( HO-1 ), an enzyme generated by stress that regulates oxidative stress and facilitates

α-Syn breakdown , therefore providing neuroprotection .

The results demonstrate that low concentrations of CO - similar to those seen in smokers — provide neuroprotection in PD models by decreasing α-Syn buildup and stimulating pathways that alleviate oxidative stress .

The findings indicate that molecular processes activated by low-dose CO may decelerate PD development , necessitating more research into its therapeutic potential . A clinical study assessing the effectiveness of low-dose carbon monoxide treatment in Parkinson ’ s disease patients is now under development .

Additionally corroborating this idea , this research revealed increased concentrations of HO-1 in the cerebral fluid of smokers relative to non-smokers . Furthermore , in post-mortem brain tissue from Parkinson ’ s disease patients , HO-1 expression was elevated in neurones without α-Syn pathology .

The results indicate that molecular pathways stimulated by low-dose CO may postpone disease onset and mitigate PD pathogenesis . Clinical research evaluating orally delivered low-dose carbon monoxide in Parkinson ’ s disease patients is proposed , given the demonstrated safety of low-dose carbon monoxide in several Phase 1 and Phase 2 clinical trials across diverse diseases .

MECHANISMS OF NEUROPROTECTION

Nicotine , a major constituent of cigarette smoke , has been thoroughly investigated for its possible neuroprotective effects . It interacts with nicotinic acetylcholine receptors ( nAChRs ), which have a role in regulating dopaminergic neurotransmission .

Research involving animals and in vitro experiments indicates that nicotine may augment dopamine release , diminish

neuroinflammation , and provide protection against oxidative stress - mechanisms pertinent to the aetiology of Parkinson ’ s disease .

Nonetheless , despite these encouraging preclinical results , recent clinical studies examining nicotine replacement treatment in Parkinson ’ s disease patients have not shown substantial diseasemodifying benefits , raising questions about nicotine ’ s significance as a principal protective component .

A further probable factor in the observed adverse relationship is carbon monoxide ( CO ), a by-product of tobacco combustion . At low concentrations , carbon monoxide ( CO ) has been shown to have cytoprotective benefits by activating heme oxygenase-1 ( HO-1 ), an enzyme that mitigates oxidative stress and promotes protein breakdown .

Recent research using mouse models of Parkinson ’ s disease indicates that lowdose carbon monoxide injection reduces α-synuclein aggregation and neuronal degeneration , offering a credible molecular rationale for the epidemiological observations .

Although biological processes provide plausible explanations , competing ideas must also be evaluated . One explanation is the “ healthy smoker effect ”, which posits that persons susceptible to Parkinson ’ s disease may be less inclined to smoke long-term owing to early , subclinical neurological symptoms that influence habit building .

Moreover , genetic and lifestyle variables obscure the association between smoking and Parkinson ’ s disease , confounding causal interpretations .

CONCLUSIONS AND DIRECTIONS

Despite epidemiological statistics indicating a reduced incidence of Parkinson ’ s disease among smokers , the precise processes are unclear , and smoking is not a feasible preventative approach owing to its established health hazards .

Future study should concentrate on finding and isolating certain protective chemicals in tobacco smoke and exploring their therapeutic potential in Parkinson ’ s disease models . A more comprehensive knowledge of these pathways may enable the creation of tailored neuroprotective therapies devoid of the detrimental consequences linked to smoking . – The HEALTH