Abstract:
:Deficiency of 5-methyltetrahydrofolate (5-MTHF) in cerebrospinal fluid (CSF) is associated with a number of neurometabolic conditions including mitochondrial electron transport chain defects. Whilst failure of the active transport of 5-methyltetrahydrofolate (5-MTHF) into the CSF compartment has been proposed as a potential mechanism responsible for the 5-MTHF deficiency seen in mitochondrial disorders, it is becoming increasingly clear that other mechanisms are involved. Here, we have considered the role of oxidative stress as a contributing mechanism. Concerning, ascorbic acid (AA), we have established a CSF reference range (103-303μM) and demonstrated a significant positive correlation between 5-MTHF and AA. Furthermore, CSF itself was also shown to convey antioxidant properties towards 5-MTHF. However, this protection could be overcome by the introduction of a hydroxyl radical generating system. Using a neuronal model system, inhibition of mitochondrial complex I, by 58%, was associated with a 23% increase in superoxide generation and a significantly increased loss of 5-MTHF from the extracellular medium. Addition of AA (150μM) was able to prevent this increased 5-MTHF catabolism. We conclude that increased generation of reactive oxygen species and/or loss of CSF antioxidants are also factors to consider with regard to the development of a central 5-MTHF deficiency. Co-supplementation of AA together with appropriate folate replacement may be of therapeutic benefit.
journal_name
Neurochem Intjournal_title
Neurochemistry internationalauthors
Aylett SB,Neergheen V,Hargreaves IP,Eaton S,Land JM,Rahman S,Heales SJdoi
10.1016/j.neuint.2013.10.002subject
Has Abstractpub_date
2013-12-01 00:00:00pages
750-5issue
8eissn
0197-0186issn
1872-9754pii
S0197-0186(13)00258-1journal_volume
63pub_type
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