The Beneficial Role of Thiamine in Parkinson Disease

Summary

Parkinson disease (PD) is the second most common form of neurodegeneration among elderly individuals. PD is clinically characterized by tremors, rigidity, slowness of movement, and postural imbalance. In this paper, we review the evidence for an association between PD and thiamine. Interestingly, a significant association has been demonstrated between PD and low levels of serum thiamine, and thiamine supplements appear to have beneficial clinical effects against PD. Multiple studies have evaluated the connection between thiamine and PD pathology, and candidate pathways involve the transcription factor Sp1, p53, Bcl‐2, caspase‐3, tyrosine hydroxylase, glycogen synthase kinase‐3β, vascular endothelial growth factor, advanced glycation end products, nuclear factor kappa B, mitogen‐activated protein kinase, and the reduced form of nicotinamide adenine dinucleotide phosphate. Thus, a review of the literature suggests that thiamine plays a role in PD, although further investigation into the effects of thiamine in PD is needed.

Introduction

Parkinson disease (PD) is a movement disorder that is characterized by tremor, rigidity, akinesia, and loss of posture reflexes, which often leads to immobility and frequent falls. PD results from the selective loss of dopaminergic (DA) neurons in the substantia nigra (SN) of the brain. Studies have suggested a relationship gbetween dopamine and thiamine, dopamine has been shown to suppress the mouse‐killing aggression (muricide) induced by a thiamine‐deficient (TD) diet 1, and this suppressive effect can be potentiated by carbidopa 2. Patients with PD who have undergone levodopa (L‐dopa) therapy show significantly higher cerebrospinal fluid (CSF) levels of thiamine diphosphate (TDP) and total thiamine than do patients who are not treated with this drug 3. Moreover, thiamine deficiency can decrease the concentration of dopamine in the striatum, whereas animals that are fed a diet containing 5% ethanol show increased dopamine turnover 4. In an animal experimental study of thiamine deficiency, region‐specific vesicular dysfunction, that is, a decreased level of dopamine metabolite, was observed posttreatment 5. Intrastriatal administration of thiamin triphosphate (TTP) or TDP has been shown to induce dopamine release 6, and thiamine derivatives are known to be present in high concentrations in the human SN 7. Dopamine release can be induced by the intrastriatal administration of TPP or TDP, reaching levels that are as high as 1400% and 249% of the basal levels, respectively, whereas reduced levels of dopamine in the striatum can occur in thiamine deficiency 6. Furthermore, decreased CSF‐free thiamine levels were noted in patients with PD as compared to controls 3. In parkinsonism‐dementia patients, thiamine pyrophosphatase activity was found to be significantly reduced in the frontal cortex 8. In addition, Gold et al. 9 reported that 70% and 33% of their patients with PD had low plasma thiamine and low RBC thiamine levels, respectively. Starvation‐induced TD encephalopathy may also cause symmetrical lesions in the SN 10. Together, these findings suggest that thiamine may play a role in DA neuron activity. Interestingly, parental thiamine administration was used successfully in 9 nonalcoholic patients who presented with acute neurological disorders 11. In addition, the administration of a combination of thiamine and acetazolamide was reported to reduce scores on the Abnormal Involuntary Movement Scale (AIMS) and the Simpson–Angus Neurological Rating Scale (ANRS) in patients with tardive dyskinesia and parkinsonism symptoms 12. Recently, thiamine has been shown to also improve the symptoms associated with PD; within days of thiamine treatment, patients reportedly had smiles on their faces, walked normally with longer strides, increased their arm swings, and experienced no tremors or sialorrhea. In addition, 3 patients no longer required carbidopa or levodopa and did not suffer ill effects on their movements. 13. In a previous publication, we identified a number of proteins that link thiamine to PD pathology 14. In the present paper, we will further discuss the relationship between thiamine and PD.

The Role of Thiamine in Parkinson Disease

The Sp1 transcription factor is a member of an extended family of DNA‐binding proteins that are acetylated in neurons in response to oxidative stress 15. The Sp1 family of proteins plays an important role in controlling the expression of the dopamine transporter gene within DA neurons 16, and these proteins also regulate the expression of the rat dopamine receptor gene 17. The rat dopamine receptor contains multiple Sp1‐binding sites 17, 18. Sp1 or another protein antigenitically related to Sp1 is included in the complex that binds the activator region of the human D_1A dopamine receptor gene 19. A novel 130‐kDa factor recognizing Sp1‐binding sequences in the D₂ gene negative modulator is also found in nuclear extract from the rat striatum 20. Furthermore, the human monoamine oxidase (MAO) B plays a major role in the degradation of biogenic and dietary amines such as phenylethylamine, benzylamine, dopamine, and tyramine. The human monoamine oxidase B gene was also regulated by Sp1 and Sp3 21. Similarly, thiamine uptake in the human intestine occurs via a specialized carrier‐mediated mechanism, and the human thiamine transporters (THTRs) are expressed in the intestine and are regulated via Sp1 promoter elements 22, 23. These findings suggest a link between thiamine, Sp1, and DA transporter and indicate that the Sp1 family of proteins plays an important role in controlling the expression of the dopamine transporter gene within DA neurons and also regulates the activity of SLC19A3 gene in transport thiamine.

The p53 gene and protein play critical roles in regulation of the normal cell cycle, cell cycle arrest, and the apoptotic response. p53 is a transcription factor that plays a major role in determining cell fates in response to DNA damage; in the central nervous system (CNS), the function of p53 is to serve as a critical regulator of neuronal cell apoptosis 24. Specifically, p53 is involved in the dopamine‐induced apoptosis of cellular granule neurons 25. In p53‐knockout mice, DA neurons were shown to be more resistant to 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced neurotoxicity than normal neurons 26, and an increase in p53 expression was observed in autopsied tissue from patients with PD 27, 28. Furthermore, levels of p53 immunoreactivity increased following 6‐hydroxydopamine (6‐OHDA)‐induced apoptosis of nigral dopaminergic neurons 29. The activation of p53 has been reported in animal models of PD, and inhibition of p53 activity was shown to prevent MPTP‐induced degeneration of DA neurons 30. These findings suggest that p53‐associated apoptosis may be a common mechanism of cell loss in several important neurodegenerative diseases. In addition, the presence of abundant p53‐immunoreactive neurites and glial cell processes appears to be a novel feature of neurodegeneration shared by these distinct diseases. Parkin is a PD‐associated gene that contributes to the functions of p53 31. Genetic depletion of endogenous parkin increases the expression, activity, and mRNA levels of p53 32. Moreover, an increased number of thiamine transporters has been observed in cells that over‐express thiamine transport genes (mTHTR‐1) and in cells exposed to conditions that induce DNA damage or p53 activation 33. TDP inhibits p53 binding, whereas thiamine inhibits intracellular p53 activity 34. In addition, the expression of p53 is significantly decreased when cultures of retinal neurons from diabetic rats are treated with thiamine 35. These observations suggest that the transcription factor p53 is activated in PD, which increases the apoptotic response to cellular damage, and that thiamine ameliorates the cellular effects of activated p53.

Bcl‐2 is a membrane‐bound protein that plays a neuroprotective role in the CNS. Bcl‐2 inhibits apoptosis and enhances the survival of newly formed neurons in the normal and ischemic hippocampus 36, and Bcl‐2 mRNA and protein expression are developmentally regulated in both the human and murine brains 37, 38. Bcl‐2 was shown to inhibit cell death caused by serum and growth‐factor withdrawal in a central neural cell line, and it has also been shown to have inhibitory effects on calcium ionophore A23187, glucose withdrawal, membrane peroxidation, and, in some cases, even free‐radical‐induced damage 39. Oxidative stress induced by the neurotoxins MPTP, paraquat, maneb, and rotenone causes lipid peroxidation and protein misfolding, which has effects on cell death through members of the Bcl‐2 family 40. MPTP‐induced DA neuron toxicity was shown to decrease the expression of Bcl‐2 in mouse SN 41, whereas Bcl‐2 over‐expression was protective against MPTP toxicity 41, 42 and 6‐OHDA toxicity 43, 44. Interestingly, high cellular concentrations of α‐synuclein have been shown to downregulate Bcl‐2 expression 45. G‐protein‐coupled receptor kinase 9 (GRK5) has been reported to accumulate in Lewy bodies, which are over‐expressed in the α‐synuclein model of PD, and regulate Bcl‐2 expression 46. In addition, glial cell‐line‐derived neurotrophic factor promoted the survival of grafted midbrain‐derived neural stem cells and increases the expression of Bcl‐2 in a rat model of PD 47. The endoplasmic reticulum (ER) chaperone σ‐1 receptor (Sig‐1R) is cytoprotective against ER stress‐induced apoptosis 48, and Sig‐1Rs are downregulated in the brains of patients with early stage PD 49. Dopamine was shown to induce apoptosis in Sig‐1R knockdown Chinese Hamster ovary cells, which could be blocked by the over‐expression of Bcl‐2 50. Therefore, decreased Bcl‐2 protein levels suggest increased levels of apoptosis in patients with PD. However, pretreatment with B vitamins (B₁, B₆, and B₁₂) had a protective effect on experimentally induced epilepsy of the mouse brain, which was associated with the induction of Bcl‐2 expression within 12 h of treatment 51. Moreover, thiamine deprivation was shown to increase cell death and reduce Bcl‐2 expression during hybridoma cell culture 52. Benfotiamine improves the functional recovery of infarcted hearts and increases Bcl‐2 protein levels 53, and it was also shown to prevent LPS‐induced apoptosis and enhance Bcl‐2 expression in a mouse macrophage cell line 54. Furthermore, when human and bovine pericytes were intermittently exposed to high levels of glucose, there was a 50–60% decrease in the Bcl‐2‐to‐Bax expression ratio, and the addition of thiamine and benfotiamine completely reversed this damaging effect 55. Altogether, these results suggest that thiamine may have a neuroprotective role in PD by increasing expression of the apoptotic inhibitor Bcl‐2.

Caspases are cysteinyl aspartate‐specific proteases that play a critical role in the regulatory and execution phases of apoptosis 56. Activation of caspases and the apoptosis of DA neurons have been implicated in the pathogenesis of PD. Activated caspases‐3 has been observed in the SN of patients with PD 57, 58, and intranigral lipopolysaccharide (LPS) injection was shown to induce the degeneration of DA neurons and increases caspase‐3 activation in the rat ventral mesencephalon 59. Glial‐cell‐line‐derived neurotrophic factors were shown to promote the survival of grafted midbrain‐derived neural stem cells, and reduce the expression of caspase‐3 in a rat model of PD 47. Moreover, caspase‐3 inhibitors were shown to protect neuronal cells from MPTP‐induced apoptosis 60, and gene disruption of caspase‐3 prevented MPTP‐induced apoptosis in the SN 61. These findings suggest that caspase‐3 activation precedes and is not a consequence of apoptotic cell death in PD. However, thiamine transporter SLC19A3 gene‐transfected breast cancer cells also demonstrated increased levels of apoptosis when exposed to doxorubicin and radiation, and this effect was partially mediated by a caspase‐3‐dependent pathway 62. Furthermore, the thiamine deficiency caused by thiamine antagonists was shown to lead to caspase‐3‐dependent apoptosis in neuronally differentiated rat PC‐12 cells 63. In addition, benfotiamine accelerated the healing of ischemic diabetic limbs in mice via the potentiation of angiogenesis and prevented the induction of pro‐apoptotic caspase‐3 64, and this compound was also shown to prevent LPS‐induced apoptosis and caspase activation in a mouse macrophage cell line 54. In addition, sulbutiamine, a highly lipid‐soluble synthetic analog of thiamine, was shown to attenuate trophic‐factor‐deprivation‐induced cell death in transformed retinal ganglion cells (RGC‐5) and decreases the expression of cleaved caspase‐3 65. These findings suggest that thiamine may play a role in PD by inhibiting the activity of the apoptotic factor caspase‐3.

Tyrosine hydroxylase (TH) is the rate‐limiting enzyme in the biosynthesis of dopamine and other catecholamines. In normal human brains, the mRNA levels of human TH_1‐2 are much greater than those of human TH_3‐4. Marked and parallel decreases in mRNA levels of human TH_1‐4 are found in the SN in PD 66. Humans and monkeys, having multiple TH isoforms, are more susceptible to MPTP than nonprimate mammals with a single form such as mice and rats, which have low susceptibility to MPTP. Such a difference may suggest the functional significance of TH isoforms in PD. The activity and protein level of TH are decreased to cause DA deficiency in the striatum in PD. However, the homo‐specific activity (activity/enzyme protein) of TH is increased. This increase in TH homo‐specific activity suggests activation by increased phosphorylation at the N‐terminus of the TH protein for a compensatory increase in DA synthesis. This compensatory activation of TH by phosphorylation in the remaining DA neurons may contribute to a further decrease in TH protein and activity in DA neurons in PD, causing a vicious circle of decreasing TH activity, protein level, and DA contents 67. mRNA level and protein content of TH are markedly decreased in the SN and striatum of the postmortem PD brain 68. The pathophysiology of PD is largely due to the nigro‐striatal DA system, as decreases in TH activity, TH synthesis, and TH mRNA levels in the striatum of patients with PD and PD animal models have been observed 69, 70. During the treatment with chronic low dose MPTP, mice developed dopamine‐dependent movement deficits induced by loss of TH‐positive nigrostriatal axon terminals 71. MPTP‐treated cats exhibited severe Parkinson‐like motor syndrome during the acute period with a marked decrease in TH‐immunoreactivity in the striatum 72. The gait variability in the PD mice showed a closer correlation with the protein levels of TH in the SN than the walking distances in the conventional open field test 73. The L‐dopa‐induced increase in striatal TH‐immunoreactive neurons is dose dependent and persists for days after L‐dopa withdrawal 74. In addition, TH gene mutations have been reported to be associated with PD; a TH heterozygous variant was reported in one patient with dopa‐responsive dystonia simulating spastic paraplegia 75 as well as in early‐onset patients with PD 76. In addition, a novel deletion in the TH gene was detected in one patients with PD 77, and decreased levels of TH protein were noted in the striatum of the MPTP‐induced neurotoxic lesions of animals with experimental PD 78. Moreover, the fluorescence intensity of TH expression was decreased in the limbic cortex and brainstem in TD mice compared with pair‐fed mice as the control group 79. In addition, male Wistar rats maintained on a TD diet demonstrated mouse‐killing behavior, which was attenuated by the administration of L‐dopa 80. Similarly, this suppressive effect was shown to be potentiated by carbidopa 2.

Glycogen synthase kinase‐3β (GSK3β) is a protein kinase that is involved in many physiological processes (e.g., metabolism, gene expression, and apoptosis). GSK3β is pivotal in controlling neuronal polarity within primary embryonic hippocampal neurons 81. GSK3β is associated with the fate of DA neurons in PD and may exert its toxicity via the induction of apoptosis by the direct activation of intrinsic cascades or via the phosphorylation of synphilin‐1 or α‐synuclein. GSK3β expression is increased in brain regions associated with PD pathology 82. In animal and cell culture models of PD, rotenone‐induced cytotoxicity is mediated by microtubule destabilization via GSK3β activation, and that microtubule destabilization is caused by reduction in the binding capacity of tau to microtubules, which is a result of tau phosphorylation via GSK3β activation. Rotenone‐induced cytotoxicity in SH‐SY5Y cells was attenuated by the GSK3β inhibitor SB216763 83. GSK3β polymorphisms alter transcription and splicing by interacting with Tau haplotypes to modify disease risk in patients with PD 84. Haplotype analysis revealed that the TT haplotype of GSK3β polymorphisms was over‐represented in patients with PD as compared to controls 85. However, GSK3β variant reduces the risk of PD in Han Chinese population 86. The GSK3 inhibitor reduces L‐dopa‐induced neurotoxicity 87, and exposure to pyrithiamine, an antithiamine compound, increases Aβ accumulation and GSK3 activity in the brain 88. In an animal model of AD, benfotiamine was shown to improve cognitive function, reduce amyloid deposition, and suppress GSK3 activity 89. These findings suggest that thiamine may play a role in PD by suppressing GSK3 activity.

Angiogenesis is a complex process that involves coordinated endothelial cell activation, proliferation, migration, tube formation, and capillary sprouting In addition, angiogenesis requires the participation of numerous intracellular signaling pathways. Vascular endothelial growth factor (VEGF) is a key mediator of angiogenesis and has been shown to have neuroprotective effects on DA neurons in models of 6‐OHDA‐induced toxicity, to decrease amphetamine‐induced rotational behavior, and to preserve TH‐positive neurons and fibers 90. In rat midbrain cultures, increased levels of VEGF‐B transcription have been reported following the addition of the neurotoxin rotenone 91, suggesting that the growth factor VEGF‐B can improve neuronal survival in a culture model of PD. An increase in the number of VEGF‐positive neurons and blood vessels was also been demonstrated in the SN of mice with MPTP‐induced neurotoxicity 92. These changes in vascularization may therefore modify the neuronal availability of blood nutrients, blood cells or toxic substances, and neuronal susceptibility to parkinsonism. Wada et al. 93 further demonstrated upregulated expression of VEGF in the SN of patients with PD. In PD animal models, the neuroprotective effects of VEGF appear to be dose dependent. Indeed, low doses of VEGF have been shown to have a neuroprotective effect on DA neurons and have been shown to result in behavioral improvement, whereas high doses have been shown to induce angiogenesis and glial proliferation 94. Moreover, thiamine deficiency was shown to result in polyneuropathy after gastrectomy, and this deficiency has also been associated with high levels of serum VEGF, which typically returned to normal following the intravenous administration of thiamine, which further improves symptoms of polyneuropathy 95. In addition, increased serum levels of VEGF have been reported in patients with wet beriberi 96. In a model of peritoneal dialysis in uremic rats, treatment with benfotiamine decreased peritoneal fibrosis, markers of inflammation, neovascularization, and VEGF staining 97. Furthermore, benfotiamine was also shown to improve the functional recovery of infarcted hearts and also reduce the phosphorylation/activation of VEGF receptor 2/Akt signaling pathways in a mouse macrophage cell line 53.

Glyoxalase 1 (Glyo‐1) catalyzes the initial rate‐limiting step in the removal of methylglyoxal (MG), which is the major precursor for advanced glycation end products (AGEs). AGEs represent a heterogeneous group of macromolecules that are formed by the nonenzymatic glycation of proteins, lipids, and nucleic acids. RAGEs are multiligand receptors, and their ligands also likely recognize several receptors to mediate their numerous biological effects 98. α‐Synuclein has been implicated in PD, and its deficiency leads to increased Glyo‐1 expression and glycation stress 99. Altered Glyo‐1 expression was also reported in brain of mouse with parkin deficiency 100. Furthermore, glycation was observed in the SN and locus ceruleus, with the greatest levels of immunoreactivity at the periphery of Lewy bodies, in patients with PD 101. In addition, AGEs were shown to stimulate the in vitro cross‐linking of α‐synuclein and accelerate intracellular inclusion body formation 102, and RAGE levels were found to be over‐expressed in patients with PD as compared to age‐matched controls 103. RAGE deficiency protects nigral DA neurons against cell death induced by the neurotoxin MPTP, and this type of cell death mimics many of the characteristic features of PD 104. Moreover, thiamine and benfotiamine supplementation prevented the tissue accumulation and increased the urinary excretion of protein glycation, oxidation, and nitration adducts associated with experimental diabetes 105. Karachalias et al. 106 reported that the hydroimidazolone of AGE residues derived from glyoxal and methylglyoxal (G‐H1 and MG‐H1) was increased by 115% and 68%, respectively, in streptozotocin‐induced diabetic rats, whereas treatment with thiamine and benfotiamine normalized these effects. However, N‐carboxymethyl‐lysine (CML) and N‐carboxyethyl‐lysine (CEL) residues increased by 74% and 118%, respectively, in diabetic‐induced rats, and only treatment with thiamine normalized these effects. In addition, serum markers of endothelial dysfunction, oxidative stress, and AGEs were shown to be increased following a meal high in AGE content, although benfotiamine significantly reduced these effects 107. The addition of benfotiamine was also shown to enhance transketolase activity and decrease the expression of AGEs and RAGEs in a model of peritoneal dialysis in uremic rats 97. In both bovine aortic endothelial cells and the retinas of diabetic rats, benfotiamine inhibited the AGE formation pathway by activating transketolase and prevented experimental diabetic retinopathy 108. Furthermore, the combined administration of thiamine and vitamin B6 to patients with diabetic nephropathy decreased DNA glycation in leukocytes, although vitamin B6 alone did not have such an effect 109.

The transcription factor nuclear factor kappa B (NF‐κB) is a hetero‐dimeric, sequence‐specific transcription factor that is found in many cell types. NF‐κB has been implicated in chronic inflammatory diseases, and it is a key regulator of genes involved in responses to infection, inflammation, and stress. Increased activation of NF‐κB has been reported in DA neurons of the SN in patients with PD as compared to controls 28, 110, 111. NF‐κB has also been identified as a component of Lewy bodies 112. A significant increase in NF‐κB was observed mainly in glial cells of the SN during MPTP‐induced apoptosis in a mouse model of PD 113. Furthermore, α‐synuclein over‐expression was shown to enhance manganese‐induced neurotoxicity via the NF‐κB‐mediated pathway 114. Selective inhibition of NF‐κB activation was shown to suppress nigral microglial activation and improve motor function in a mouse model of PD 115, and benfotiamine was also shown to inhibit NF‐κB activation, via the activation of transketolase, and prevent experimental diabetic retinopathy in both bovine aortic endothelial cells and the retinas of diabetic rats 108. Benfotiamine was further shown to prevent endotoxin‐induced inflammation by suppressing oxidative‐stress‐induced NF‐κB activation in rats with endotoxin‐induced uveitis and in murine macrophage cell lines 54, 116, and benfotiamine‐mediated suppression of expression of NF‐κB prevented LPS‐induced macrophage cell death and monocyte adhesion to endothelial cells 117. Altogether, these findings indicate that thiamine may suppress NF‐κB activation in PD.

The mitogen‐activated protein kinase (MAPK) pathways provide a key link between membrane‐bound receptors and changes in gene expression, involving the extracellular signal‐regulated kinase (ERK) cascade, the stress‐activated protein kinases/c‐jun N‐terminal kinase (SAPK/JNK) cascade, and the p38 MAPK/RK/HOG cascade 118. Increased cytoplasmic ERK1/2 activity has been observed in the brains of human patients with PD 119, and degenerating SN neurons typically display phosphorylated‐ERK1/2 granules 120. The activation of ERK1/2 is induced by the neurotoxin 6‐OHDA, and inhibition of ERK activation enhances neuronal survival 121, 122. The mitochondrial localization of ERK2 activity suggests an effect of 6‐OHDA on mitophagy and autophagic cell death in PD 123. Dysregulation of the autophagy pathway has been observed in the brains of patients with PD and in animal models of PD 124, 125. In addition, the activation of p38 MAPK has been demonstrated in the SN of MPTP‐treated mouse models of PD 126. Moreover, vulnerability to glutamate‐induced toxicity in DA neurons is dependent on endogenous dopamine as well as MAPK activation 126. Interestingly, genetic deficiency in MAPK kinase 2^−/− prevented MPTP‐induced neurotoxicity in mouse models of PD 127. Moreover, benfotiamine was shown to modulate the macrophage response to bacterial endotoxin‐induced inflammation by preventing the activation of p‐38 MAPK and stress‐activated kinases (SAPK/JNK) 54.

The reduced form of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) enzyme complex mediates critical physiological and pathological processes including cell signaling, inflammation, and mitogenesis, by generating reactive oxygen species (ROS) from molecular oxygen. NOX is widely expressed in various immune cells, including microglia, macrophages, and neutrophils. NOX expression was observed in the nuclei of DA neurons in the SN of patients with PD and animals with 6‐OHDA‐induced neurotoxicity 128. NOX activation was reported to increase zinc‐induced DA neurodegeneration as well as MPPT, rotenone, angiotensin, and paraquat‐induced neurotoxicity in animal models of PD 129, 130, 131, 132, 133. Inhibition and knockdown of NOX were shown to reduce paraquat‐induced ROS generation and DA cell death 133, and NOX inhibitors were also shown to protect against LPS‐induced toxicity, MPPT‐induced oxidative stress, and apoptosis in mesencephalic DA neuronal cells 134, 135. Thiamine is an essential coenzyme for transketolase, which is part of the pentose phosphate pathway that helps maintain cellular NADPH levels. In a study that administered glyoxal toxicity to hepatocytes, thiamin demonstrated cytoprotective functions and restored NADPH levels, glyoxal detoxification, and mitochondrial membrane potential 136. Furthermore, NADPH‐cytochrome c reductase levels were increased in TD animals 137, and benfotiamine treatment under both normo‐ and hyper‐glycemic conditions significantly downregulated Nox4 expression 138. In addition, animals that were fed a high‐thiamine diet had approximately 57% of the NADPH‐cytochrome c reductase activity of those that were fed a TD diet 139. Altogether, these results suggest that thiamine may be neuroprotective against PD by regulating NADPH‐cytochrome c activity.

Conclusions

Thiamine plays a beneficial role in PD by inducing dopamine release and improving the symptoms associated with PD. Genetic studies have provided the opportunity to identify the specific proteins that link thiamine to the pathology of PD. Thiamine also exerts its effects on PD via nongenomic mechanisms. In addition, thiamine involved in PD, including the DJ‐1 gene, excitatory amino acid transporters (EAATs), the α‐ketoglutarate dehydrogenase complex, coenzyme Q10, lipoamide dehydrogenase, chromosome 7, transcription factor p53, the renin–angiotensin system, heme oxygenase‐1, and poly(ADP‐ribose) polymerase‐1 gene 14. However, gastrointestinal dysfunction is common in patients with PD, and it potentially affects the therapeutic intervention 140. Gastric emptying has been reported to be frequently delayed in patients with PD 141. Decreased nonmediated uptake across the enterocyte brush border membrane was demonstrated in patients with PD 142. In addition, the intestinal absorption of thiamine is sufficient in young people but may be reduced with age 143. Parental administration of thiamine may be suitable for patients with PD 14. Thus, further studies are needed to determine the potential benefits of using thiamine as a treatment for PD.

Funding

The authors, Dr. Khanh Luong and Dr. Lan Nguyen, received no funding for this study.

Conflict of Interest

The authors declare no conflict of interest.