1,25‐Dihydroxyvitamin D3 exerts neuroprotective effects in an ex vivo model of mild hyperhomocysteinemia

Abstract

Elevated plasma homocysteine (Hcy) levels have been detected in patients with various neurodegenerative conditions. Studies of brain tissue have revealed that hyperhomocysteinemia may impair energy metabolism, resulting in neuronal damage. In addition, new evidence has indicated that vitamin D plays crucial roles in brain development, brain metabolism and neuroprotection. The aim of this study was to investigate the neuroprotective effects of 1,25-dihydroxivitamin D3 (calcitriol) in cerebral cortex slices that were incubated with a mild concentration of Hcy. Cerebral cortex slices from adult rats were first pre-treated for 30 min with one of three different concentrations of calcitriol (50 nM, 100 nM and 250 nM), followed by Hcy for 1h to promote cellular dysfunction. Hcy caused changes in bioenergetics parameters (e.g., respiratory chain enzymes) and mitochondrial functions by inducing changes in mitochondrial mass and swelling. Here, we used flow cytometry to analyze neurons that were double-labelled with Propidium Iodide (PI) and found that Hcy induced an increase in NeuN(+)/PI cells but did not affect GFAP(+)/Pi cells. Hcy also induced oxidative stress by increasing reactive oxygen species generation, lipid peroxidation and protein damage and reducing the activity of antioxidant enzymes (e.g., SOD, CAT and GPx). Calcitriol (50 nM) prevented these alterations by increasing the level of the vitamin D receptor. Our findings suggest that using calcitriol may be a therapeutic strategy for treating the cerebral complications caused by Hcy.

Role of Homocysteine in the Ischemic Stroke and Development of Ischemic Tolerance

“…This enzyme belongs to the first line of cellular defense against oxidative injury and has been observed to be diminished in the hHcy group compared to the control group. These results are consonant with very recent experiments of Longoni et al (2016), which also emphasize a high potency of hHcy conditions for putative posttranslational Hcy induced protein modifications. This likely could lead to enzyme(s) homocysteinylation and thiolation which might contribute to the partial enzyme inactivation.…”

“…Similarly, results from hHcy experiments (Longoni et al, 2016) pointed out the neuroprotective effect of vitamin D (calcitriol) against hHCy as an important factor of brain development, brain metabolism and neuroprotection. The authors showed that pre-treatment with calcitriol up to 250 nmol/l has a remarkable protective effect on cortical slices.…”

Implications of Oxidative Stress and Potential Role of Mitochondrial Dysfunction in COVID-19: Therapeutic Effects of Vitamin D

“…In vitro studies on cerebral cortices from rats pre-treated with calcitriol and exposed to a mild concentration of homocysteine, demonstrated that altered bioenergetics parameters and impaired mitochondrial functions promoted by homocysteine were significantly attenuated by pre-treatment with calcitriol. Specifically, calcitriol reduced the concentration of ROS and lipid peroxidation and increased the antioxidant enzyme activity, preventing changes in mitochondrial brain cell [89]. This same protective antioxidant effect of vitamin D against hyperhomocysteinemia was observed in heart tissue, where the accumulation of homocysteine may contribute to the development of cardiovascular disease [90].…”

Calcitriol Reduces Adverse Effects of Diclofenac on Mitochondrial Function in Isolated Rat Heart Mitochondria

“…However, doses up to 10 000 IU have not been shown to cause toxicity in healthy individuals [36]. Recently, there are several studies that showed calcitriol acts as a mitochondrial protective agent and antioxidant, preventing the oxidative damage induced by homocysteine in rats [26,37]. Despite the life-threatening cardiotoxicity of DIC, up to date, there is no known reversal agent for cardiotoxicity induced by DIC.…”