Calcitriol Promotes Augmented Dopamine Release in the Lesioned Striatum of 6-Hydroxydopamine Treated Rats

Abstract

Current therapies for Parkinson's disease (PD) offer symptomatic relief but do not provide a cure or slow the disease process. Treatments that could halt progression of the disease or help restore function to damaged neurons would be of substantial benefit. Calcitriol, the active metabolite of vitamin D, has been shown to have significant effects on the brain. These effects include upregulating trophic factor levels, and reducing the severity of some central nervous system lesions. While previous studies have shown that calcitriol can be neuroprotective in 6-hydroxydopamine (6-OHDA) rodent models of PD, the present experiments were designed to examine the ability of calcitriol to promote restoration of extracellular DA levels and tissue content of DA in animals previously lesioned with 6-OHDA. Male Fischer-344 rats were given a single injection of 12 µg 6-OHDA into the right striatum. Four weeks later the animals were administered vehicle or calcitriol (0.3 or 1.0 µg/kg, s.c.) once a day for eight consecutive days. Three weeks after the calcitriol treatments in vivo microdialysis experiments were conducted to measure potassium and amphetamine evoked overflow of DA from both the left and right striata. In control animals treated with 6-OHDA and vehicle there were significant reductions in both potassium and amphetamine evoked overflow of DA on the lesioned side of the brain compared to the contralateral side. In animals treated with 6-OHDA followed by calcitriol there was significantly greater potassium and amphetamine evoked overflow of DA from the lesioned striatum compared to that from the control animals. The calcitriol treatments also led to increases in postmortem tissue levels of DA in the striatum and substantia nigra. These results suggest that calcitriol may help promote recovery of dopaminergic functioning in injured nigrostriatal neurons.

Vitamin D regulates tyrosine hydroxylase expression: N-cadherin a possible mediator

“…Progression of PD symptoms is associated with the degeneration of dopaminergic neurons. As previously outlined, preclinical studies in neurotoxicity animal models of this disease confirm that 1,25(OH) 2 D 3 can restore dopamine levels in striatum and ameliorate dopamine neuron death induced by intra-cerebral administration of 6-OHDA (Wang et al, 2001;Smith et al, 2006;Sanchez et al, 2009;Cass et al, 2012Cass et al, , 2014. Cass et al and Sanchez et al have showed that vitamin D increases GDNF in the lesioned striatum indicating this trophic agent may be the mediating factor for vitamin D's neuroprotective actions on dopamine neurons.…”

“…A number of studies have shown that 1,25(OH) 2 D 3 can act as a neuroprotective agent for dopaminergic neurons (Wang et al, 2001;Cass et al, 2006;Smith et al, 2006;Sanchez et al, 2009;Cass et al, 2012Cass et al, , 2014. These data and the epidemiological findings linking low levels of vitamin D with increased risk of Parkinson's disease (PD) (Newmark and Newmark, 2007;Evatt et al, 2008Evatt et al, , 2011Knekt et al, 2010;Peterson et al, 2013) have led to a clinical trials of vitamin D in this disease.…”

“…Multiple studies have shown that treatment with the active form of vitamin D, 1,25(OH) 2 D 3 , protects against the adverse effects of the well-known dopaminergic toxin, 6-hydroxydopamine (6-OHDA) (Wang et al, 2001;Smith et al, 2006;Cass et al, 2012Cass et al, , 2014. Cass et al showed that long-term 1,25(OH) 2 D 3 treatment increases the level of glial-derived neurotrophic factor (GDNF) in the damaged striatum.…”

“…In addition to its well-known trophic actions on dopaminergic neurons, GDNF has also been found to be able to restore evoked dopamine levels after 6-OHDAinduced striatal damage (Cass and Manning, 1999). It was postulated that GDNF at least partially contributed to the protective effect of 1,25(OH) 2 D 3 in these animal models Cass et al, 2014). Interestingly, although it has been suggested that tyrosine hydroxylase (TH), a rate limiting enzyme for dopamine synthesis, might be directly modulated by 1,25(OH) 2 D 3 this was never established.…”

Vitamin D protects dopaminergic neurons against neuroinflammation and oxidative stress in hemiparkinsonian rats

“…The mechanism by which VD3 promotes recovery of dopaminergic release and content remains to be determined, but evidences indicated its potential for affecting calcium metabolism, apoptosis, inflammation, immunomodulation, detoxification, and upregulation of neurotrophins [51–53]. …”