Interestingly, neonatal handling could prevent Vit C reduction in rats exposed to chronic moderate stress in adulthood. this review is to update the current state of knowledge of the role of vitamin C on neurodegenerative diseases including Alzheimers disease, Parkinsons disease, Huntingtons disease, multiple sclerosis and amyotrophic sclerosis, as well as psychiatric disorders including depressive disorder, anxiety and schizophrenia. The particular attention is attributed to understanding of the mechanisms underlying possible therapeutic properties of ascorbic acid in the presented disorders. or [84,85]. Different mechanisms, including genomic factors, epigenetic changes, toxic factors, mitochondrial dysfunction, oxidative stress, neuroimmune/neuroinflammatory reactions, hypoxic-ischemic conditions, metabolic deficiencies and ubiquitinCproteasome system dysfunction, seem to be involved in PD pathogenesis [84,86,87,88,89,90,91,92]. Mitochondrial dysfunction has been shown to be linked to mutations in and genes [87,88]. Moreover, it is known that dopamine metabolism produces oxidant species, whereas oxidative stress participates in protein aggregation in PD [22,90,93]. Glutamate-mediated excitotoxicity has been proposed to be a further PD factor. It is also suggested that, like in the case of AD, PD might be a prion-like disease [94,95,96]. Olanow et al. [94] proposed the hypothesis that -synuclein is usually a prion-like protein that can adopt a self-propagating conformation and thereby cause neurodegeneration. Scheffold et al. [97], in turn, reported that telomere shortening (one of the hallmarks of ageing) led to an acceleration of synucleinopathy and impaired microglia response and thereby might contribute to PD pathology. It is likely that not the above factors per se, but rather their synergistic interactions result in the development of the nigrostriatal damage in PD. Vit C is usually believed to play a role in dopaminergic neuron differentiation. He et al. [98] in in vitro study found that Vit C enhanced the differentiation of midbrain derived neural stem cell towards dopaminergic neurons by increasing 5-hydroxymethylcytosine (5hmC) and decreasing histone H3 lysine 27 tri-methylation (H3K27m3) generation in dopamine phenotype gene promoters, which are catalyzed by ten-eleven-translocation 1 methylcytosine dioxygenase 1 (Tet1) and histone H3K27 demethylase (Jmjd3), respectively [98,99]. It seems that Vit C acts through regulation of Tet1 and Jmjd3 activities (it acts as a co-factor), since Tet1 and Jmjd3 knockdown/inhibition resulted in no effect of Vit C on either 5hmC or H3K27m3 in the progenitor cells [98]. In another in vitro Sstr1 study, it was shown that mouse embryonic fibroblasts cultured in Vit C-free medium displayed extremely low content of 5hmC, whereas treatment with Vit C resulted in a dose- and time-dependent increase in 5-hmC generation, which was not associated with any change in genes expression. Additionally, it was found that treatment with another reducing agent as glutathione did not affect 5-hmC, whereas blocking Vit C entry into cells or knocking down expression significantly reduced the effect of Vit C on 5-hmC [100]. Vit C is also believed to play an indirect role in -syn oligomerization. Posttranslational -syn modifications caused by oxidative stress, including modification by 4-hydroxy-2-nonenal, nitration and oxidation, have been implicated to promote oligomerization of -syn, whereas Vit C as an antioxidant prevents this effect [22,101]. Jinsmaa et al. [102] found that treatment with Vit C attenuated Cu2+-mediated augmentation of 3,4-dihydroxyphenylacetaldehyde (DOPAL)-induced -syn oligomerization in rat pheochromocytoma PC12 cells, but alone (without Cu2+) did not exert such an effect. Khan et al. showed, in turn, that Vit C supplementation (227.1 M, 454.2 M or 681.3 M in diet, 21 days) caused a significant dose-dependent delay in the loss of climbing ability of PD Drosophila model expressing normal human -syn in the neurons [103]. Moreover, Vit C is usually thought to be involved in neuroprotection against glutamate-mediated excitotoxicity occurring in PD. Ballaz et al. [104] in in vitro study performed on dopaminergic neurons of human origin showed that Vit C prevented cell death following prolonged exposure to glutamate. Glutamate induced toxicity in a dose-dependent way via the stimulation of -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and metabotropic receptors and to a lesser degree by = 37) in comparison with healthy subjects. The intake of Vit C in both groups was below.[149], in turn, suggested that the use of Vit C could have an unfavorable effect in ALS patients. amyotrophic sclerosis, as well as psychiatric disorders including depressive disorder, stress and schizophrenia. The particular attention is attributed to understanding of the mechanisms underlying possible therapeutic properties of ascorbic acid in the presented disorders. or [84,85]. Different mechanisms, including genomic factors, epigenetic changes, toxic factors, mitochondrial dysfunction, oxidative stress, neuroimmune/neuroinflammatory reactions, hypoxic-ischemic conditions, metabolic deficiencies and ubiquitinCproteasome system dysfunction, seem to be involved in PD pathogenesis [84,86,87,88,89,90,91,92]. Mitochondrial dysfunction has been shown to be linked to mutations in and genes [87,88]. Moreover, it is known that dopamine metabolism produces oxidant species, whereas oxidative stress participates in protein aggregation in PD [22,90,93]. Glutamate-mediated excitotoxicity has been proposed to be a further PD factor. It is also suggested that, like in the case of AD, PD might be a prion-like disease [94,95,96]. Olanow et al. [94] proposed the hypothesis that -synuclein is usually a prion-like protein that can adopt a self-propagating conformation and thereby cause neurodegeneration. Scheffold et al. [97], in turn, reported that telomere shortening (one of the hallmarks of ageing) led to an acceleration of synucleinopathy and impaired microglia response and thereby might contribute Cefozopran to PD pathology. It is likely that not the above factors per se, but rather their synergistic interactions result in the development of the nigrostriatal damage in PD. Vit C is usually believed to play a role in dopaminergic neuron differentiation. He et al. [98] in in vitro research discovered that Vit C improved the differentiation of midbrain produced neural stem cell towards dopaminergic neurons by raising 5-hydroxymethylcytosine (5hmC) and reducing histone H3 lysine 27 tri-methylation (H3K27m3) era in dopamine phenotype gene promoters, that are catalyzed by ten-eleven-translocation 1 methylcytosine dioxygenase 1 (Tet1) and histone H3K27 demethylase (Jmjd3), respectively [98,99]. It appears that Vit C functions through rules of Tet1 and Jmjd3 actions (it functions like a co-factor), since Tet1 and Jmjd3 knockdown/inhibition led to no aftereffect of Vit C on either 5hmC or H3K27m3 in the progenitor cells [98]. In another in vitro research, it was demonstrated that mouse embryonic fibroblasts cultured in Vit C-free moderate displayed incredibly low content material of 5hmC, whereas treatment with Vit C led to a dosage- and time-dependent upsurge in 5-hmC era, which was not really connected with any modification in genes manifestation. Additionally, it had been discovered that treatment with another reducing agent as glutathione didn’t influence 5-hmC, whereas obstructing Vit C admittance into cells or knocking down manifestation significantly reduced the result of Vit C on 5-hmC [100]. Vit C can be thought to play an indirect part in -syn oligomerization. Posttranslational -syn adjustments due to oxidative tension, including changes by 4-hydroxy-2-nonenal, nitration and oxidation, have already been implicated to market oligomerization of -syn, whereas Vit C as an antioxidant prevents this impact [22,101]. Jinsmaa et al. [102] discovered that treatment with Vit C attenuated Cu2+-mediated enhancement of 3,4-dihydroxyphenylacetaldehyde (DOPAL)-induced -syn oligomerization in rat pheochromocytoma Personal computer12 cells, but only (without Cu2+) didn’t exert this impact. Khan et al. demonstrated, subsequently, that Vit C supplementation (227.1 M, 454.2 M or 681.3 M in diet plan, 21 Cefozopran times) caused a substantial dose-dependent hold off in the increased loss of climbing ability of PD Drosophila magic size expressing normal human being -syn in the neurons [103]. Furthermore, Vit C can be regarded as involved with neuroprotection against glutamate-mediated excitotoxicity happening in PD. Ballaz et al. [104] in in vitro research performed on dopaminergic neurons of human being origin demonstrated that Vit C avoided cell death pursuing prolonged contact with glutamate. Glutamate induced toxicity inside a dose-dependent method via the excitement of -amino-3-hydroxy-5-methyl-4-isoxazole propionic acidity (AMPA) and metabotropic receptors also to a lesser level by = 37) in comparison to healthy subjects. The consumption of Vit C in both organizations was below nutritional guide intake (DRI), in charge group it had been close to the DRI worth however. An effectiveness of antioxidant therapy in relapsing-remitting multiple sclerosis individuals (= 14) treated with complicated of antioxidants and neuroprotectors with different systems of actions (oc-lipoic acidity, nicotinamide, acetylcysteine, triovit beta-carotine, alpha-tocopheryl acetate, ascorbic acidity, selenium, pentoxifylline, cerebrolysin, amantadine hydrochloride) during one month, 2 moments a complete year was investigated by Cefozopran Odinak et al. [140]. The procedure led to significant reduced amount of relapse rate of recurrence, loss of required corticosteroid programs and reduced content material of lipid peroxide items [140] significantly. Nevertheless, it ought to be underlined that Vit C was only 1 part of multicomponent treatment. Nevertheless, in another scholarly research it had been demonstrated that intrahippocampal.