Riboflavin Has Neuroprotective Potential: Focus on Parkinson's Disease and Migraine

Abstract

With the huge negative impact of neurological disorders on patient's life and society resources, the discovery of neuroprotective agents is critical and cost-effective. Neuroprotective agents can prevent and/or modify the course of neurological disorders. Despite being underestimated, riboflavin offers neuroprotective mechanisms. Significant pathogenesis-related mechanisms are shared by, but not restricted to, Parkinson's disease (PD) and migraine headache. Those pathogenesis-related mechanisms can be tackled through riboflavin proposed neuroprotective mechanisms. In fact, it has been found that riboflavin ameliorates oxidative stress, mitochondrial dysfunction, neuroinflammation, and glutamate excitotoxicity; all of which take part in the pathogenesis of PD, migraine headache, and other neurological disorders. In addition, riboflavin-dependent enzymes have essential roles in pyridoxine activation, tryptophan-kynurenine pathway, and homocysteine metabolism. Indeed, pyridoxal phosphate, the active form of pyridoxine, has been found to have independent neuroprotective potential. Also, the produced kynurenines influence glutamate receptors and its consequent excitotoxicity. In addition, methylenetetrahydrofolate reductase requires riboflavin to ensure normal folate cycle influencing the methylation cycle and consequently homocysteine levels which have its own negative neurovascular consequences if accumulated. In conclusion, riboflavin is a potential neuroprotective agent affecting a wide range of neurological disorders exemplified by PD, a disorder of neurodegeneration, and migraine headache, a disorder of pain. In this article, we will emphasize the role of riboflavin in neuroprotection elaborating on its proposed neuroprotective mechanisms in opposite to the pathogenesis-related mechanisms involved in two common neurological disorders, PD and migraine headache, as well as, we encourage the clinical evaluation of riboflavin in PD and migraine headache patients in the future.

Keywords: Parkinson’s disease; glutamate excitotoxicity; homocysteine; kynurenine; migraine; oxidative stress; pyridoxal phosphate; riboflavin.

Figure 1

Riboflavin protects against neurotoxicity through ameliorating oxidative stress, mitochondrial dysfunction, neurogenic inflammation, glutamate excitotoxicity, and homocysteine neurotoxicity. Oxidative stress, mitochondrial dysfunction, neurogenic inflammation, glutamate excitotoxicity, and homocysteine neurotoxicity are involved in neurodegeneration and neurotoxicity. Also, those neurotoxic factors have the ability to cause each other leading to the formation of a neurotoxic cycle. Riboflavin is capable of attacking this proposed neurotoxic cycle via multiple neuroprotective mechanisms that tackle different neurotoxic factors in this neurotoxic cycle. (A) In fact, riboflavin attacks oxidative stress via its antioxidant potential. First, glutathione reductase requires riboflavin for its action to reduce oxidized glutathione increasing the levels of reduced (active) glutathione. Second, riboflavin has independent antioxidant action through its reduced form (dihydroriboflavin). Third, riboflavin has the ability to elevate antioxidant enzymes levels such as SOD and catalase. Fourth, riboflavin is required for the formation of pyridoxal phosphate (PLP), the active vitamin B6, which has its own antioxidant activity (see Riboflavin Is Required for the Formation of Pyridoxal Phosphate). (B) In addition, riboflavin attacks neurogenic inflammation either directly or indirectly. Riboflavin has the ability to inhibit NF-κB and high-mobility group protein B1 (HMGB1), nuclear factors involved in inflammatory processes, demonstrating its direct anti-inflammatory activity. On the other hand, multiple enzymes in the biosynthetic pathway of vitamin D are riboflavin-dependent enzymes, thus, riboflavin exerts its indirect anti-inflammatory activity via its essential role in vitamin D synthesis, which has a potent anti-inflammatory activity. (C) Furthermore, administration of riboflavin is capable of elevating the intra-mitochondrial levels of flavin adenine dinucleotide (FAD), which will compensate for the reduced capacity of dysfunctional complexes to assemble. As a result, riboflavin aims to normalize mitochondrial function in dysfunctional states. (D) Moreover, elevated homocysteine levels exhibit neurotoxic effects. Riboflavin-dependent enzymes are critical steps in the synthesis of methyltetrahydrofolate (MTHF) and PLP. MTHF and PLP are required for the actions of homocysteine metabolizing enzymes; methionine synthase and cystathionine b-synthase, respectively (see Riboflavin Is Required for Homocysteine Metabolism). (E) Additionally, riboflavin has the ability to attack glutamate excitotoxicity. In fact, riboflavin inhibits the endogenous neuronal release of glutamate reducing its excitotoxicity potential. In addition, both riboflavin and PLP (riboflavin is required for its synthesis) have their intrinsic protective properties against glutamate toxicity by increasing the survival of neurons exposed to glutamate toxicity after being treated with riboflavin or PLP. Also, both riboflavin and PLP are essential determinants of the tryptophan–kynurenine pathway, which produce neuroactive compounds known as kynurenines that influences glutamate receptors, hence, modulating glutamate excitotoxicity potential (see Riboflavin as a Determinant of the Kynurenine Pathway and Riboflavin Can Ameliorate Glutamate Toxicity; Which Is Implicated in Parkinson’s Disease and Migraine).

Figure 2

Riboflavin is required for the formation of Pyridoxal phosphate (68). Pyridoxine, pyridoxal, and pyridoxamine are forms of vitamin B6 (vitamin B6 vitamers). Through pyridoxine kinase, those vitamers will form pyridoxine 5′-phosphate, pyridoxal 5′-phosphate, pyridoxamine 5′-phosphate, respectively. These reactions are reversible with phosphatases. Pyridoxal 5′-phosphate (PLP) is the active form of vitamin B6. Consequently, pyridoxine 5′-phosphate and pyridoxamine 5′-phosphate must be converted to PLP. Pyridoxine phosphate oxidase (PNPO) is the enzyme required for this conversion and formation of the active PLP from pyridoxine and pyridoxamine. PNPO requires riboflavin (B2) as its main cofactor.

Figure 3

Riboflavin is an essential determinant of the kynurenine pathway (73). Kynurenine pathway is the main tryptophan catabolism pathway, with neuroactive metabolites known as kynurenines. This pathway is determined by vitamin B2 status, indicated by plasma riboflavin, and B6 status, indicated by circulating PLP; since both vitamins are essential cofactors. Flavin adenine dinucleotide is required for the formation of 3-hydroxykynurenine. PLP is required for the formation of anthranilic acid, 3-hydroxyanthranilic acid, kynurenic acid, and xanthurenic acid. TDO, tryptophan 2,3-dioxygenase; IDO, indoleamine 2,3-dioxygenase; KAT, kynurenine aminotransferase; KYNU, kynureninase; KMO, kynurenine 3-monooxygenase; PLP, pyridoxal phosphate; B2, riboflavin.

Figure 4

Riboflavin has essential role in homocysteine metabolic pathways of re-methylation and transsulfuration. (A) Homocysteine undergoes re-methylation forming methionine through MS which requires methylated b12. The methyl group is donated from 5-methyltetrahydrofolate, synthesized via action of the riboflavin-dependent enzyme MTHFR on 5,10-methylenetetrahydrofolate. (B) The second fate of homocysteine is to undergo transsulfuration through CBS forming cystathionine and glutathione. This pathway requires PLP as a cofactor. PLP requires riboflavin for its synthesis from vitamin B6 phosphorylated vitamers. THF, tetrahydrofolate; 5,10-MTHF, 5,10-methenyltetrahydrofolate; MTHFR, methylenetetrahydrofolate reductase; 5-MTHF, 5-methyltetrahydrofolate; B12, cobalamin; MS, methionine synthase; SAM-e, S-adenosyl methionine; SAH, S-adenosylhomocysteine; PLP, pyridoxal phosphate; CBS, cystathionine b-synthase; PNPO, pyridoxine/pyridoxamine phosphate oxidase; PMP, pyridoxamine phosphate; PNP, pyridoxine phosphate.