# Vitamin D and Rehabilitation after Stroke: Status of Art
## 2 Vitamin D Metabolism  
Vitamin D is a hormone involved in calcium metabolism and bone homeostasis and has a significant function in immune modulation, cell growth regulation, cell proliferation and differentiation [13; 16]. Vitamin D (named also calciferol) is provided predominantly through dermis exposure to sunlight and in the smallest portions through intake from diet (food and vitamin supplements). In the skin, 7-dehydrocholesterol (provitamin D3) is converted into pre-cholesterol (previtamin D3) by UV light and then modified into cholecalciferol (vitamin D3). The dietary source of vitamin D is in the form of ergocalciferol (vitamin D2). Cholecalciferol and ergocalciferol are prohormones transported into the blood by vitamin-D-binding protein (VDBP) but to become active they must be hydroxylated. Once transported in the liver, vitamin D2 and D3 are hydroxylated by the cytochrome P450 mixed-function oxidases, encoded by _CYP2R1_, and located at endoplasmic reticulum, generating the 25 hydroxy vitamin D [25(OH)D], or calcidiol (in this review we will not differentiate between 25(OH)D2 or 25(OH)D3) [5] (Figure 1). In the renal tubules of the kidney, 25(OH)D is further hydroxylated by 1 \(\alpha\)-hydroxylase encoding by _CYP2R1_ and generating 1,25 dihydroxy vitamin D (1,25(OH)\({}_{2}\) D or calcitriol) [17; 18]. The 1,25(OH)\({}_{2}\)D (calcitriol), the biologically active molecule, has chemical similarities with typical steroid hormones like estrogen, testosterone and cortisol. 1,25(OH)\({}_{2}\)D production is downregulated by high levels of calcium and phosphate, while it is upregulated by high levels of the parathyroid hormone (PTH), secreted by the parathyroid glands [5]. The _CYP2A1_ gene codes for a 24-hydroxylase enzyme which is able to inactivate both 25(OH)D and 1,25(OH)D via hydroxylation [18]. Once secreted by the kidney, 1,25(OH)\({}_{2}\)D is bound by VDBP and it reaches the target organs where the Vitamin D receptor (VDR) mediates its absorption. VDR, encoded by the _VDR_ gene, is a crucial receptor of the vitamin D endocrine and autocrine systems (Figure 1). The expression of VDR is ubiquitous. In particular, this receptor is highly expressed in several tissue and cell types such as the small intestine, colon, kidney, bone, skin, the vascular system, endocrine organs, immune system, brain and muscle, with a probable involvement of VDR in the pathophysiology of various diseases, such as several autoimmune disorders, various malignancies, and cardiovascular risk factors [19]. Recent studies suggested an important role of VDR in the molecular physiology of ischemic stroke [20]. Moreover, this VDR is also expressed in the central nervous system, especially in the hippocampus, allowing a high absorption of Vitamin D in this brain district; this evidence argues in favor of a neuroprotective effect exerted by Vitamin D [21]. _Biochemical Measurements and Dietary Intake_  
Plasma or serum concentration of 25(OH)D is the universally accepted biomarker of vitamin D status. With respect to the other metabolites, 25(OH)D properly reflects the nutritional vitamin D status, having the longest half-life between 2 and 3 weeks; cholecaliferol (Vitamin D3) has a half-live of 24 h, while 1,25(OH)\({}_{2}\)D has a half-life of only 4 h.  
The higher percentage of 25(OH)D and 1,25(OH)\({}_{2}\)D in circulation is bound to VDBP (80-90%) and albumin (10-20%); however, a small portion is free (0.02-0.05% of 25(OH)D and 0.2-0.6% of 1,25(OH)\({}_{2}\)D). There is not a consensus on the optimal 25(OH)D values and two major official reports were published from the Institute of Medicine (IOM) [22] and Endocrine Society [23]. Figure 1: Absorption and metabolism of Vitamin D in human body. Skin or diet: 7-dehydrocholesterol (provitamin D3) is converted into pre-cholesterol (previtamin D3) by UV light and then modified into cholecaliferol (vitamin D3). The dietary source of vitamin D is ergocalciferol (vitamin D2).