Vitamin D deficiency reduces the benefits of progesterone treatment after brain injury in aged rats

Abstract

Administration of the neurosteroid progesterone (PROG) has been shown to be beneficial in a number of brain injury models and in two recent clinical trials. Given widespread vitamin D deficiency and increasing traumatic brain injuries (TBIs) in the elderly, we investigated the interaction of vitamin D deficiency and PROG with cortical contusion injury in aged rats. Vitamin D deficient (VitD-deficient) animals showed elevated inflammatory proteins (TNFα, IL-1β, IL-6, NFκB p65) in the brain even without injury. VitD-deficient rats with TBI, whether given PROG or vehicle, showed increased inflammation and greater open-field behavioral deficits compared to VitD-normal animals. Although PROG was beneficial in injured VitD-normal animals, in VitD-deficient subjects neurosteroid treatment conferred no improvement over vehicle. A supplemental dose of 1,25-dihydroxyvitamin D3 (VDH) given with the first PROG treatment dramatically improved results in VitD-deficient rats, but treatment with VDH alone did not. Our results suggest that VitD-deficiency can increase baseline brain inflammation, exacerbate the effects of TBI, and attenuate the benefits of PROG treatment; these effects may be reversed if the deficiency is corrected.

A Combination Therapy of Nicotinamide and Progesterone Improves Functional Recovery following Traumatic Brain Injury

“…We are not the first to combine relevant combinations of treatments to administer following injury. There have been other instances of combination treatments showing benefit in the past, [64][65][66][67][68][69][70] including a combination of Prog and vitamin D. 64,65,68 In conclusion, we have demonstrated that a combination treatment of NAM and Prog provides improved neuroprotection and recovery of function in a variety of sensorimotor tasks, compared with NAM or Prog treatment alone. The current study provides a good initial assessment of the combination of NAM and Prog in a preclinical trial of controlled cortical impact of the sensorimotor cortex of the rat.…”

A Functional Relay from Progesterone to Vitamin D in the Immune System

“…There is a report that the protective efficacy of P4 was significantly decreased in vit. D deficiency (Cekic et al, 2011), indicating that the neuroprotective function of P4 depends on vit. D availability.…”

The role of adult vitamin D deficiency in cognition and brain function in mice

“…Vitamin D-deficient rats with traumatic brain injury show increased inflammation and greater open field test behavioural deficits in comparison with controls (Cekic et al, 2011). Although progesterone, a neurosteroid that has been beneficial as a treatment in traumatic brain injury in recent clinical trials (Wright et al, 2007;Xiao et al, 2008), was beneficial in injured control animals, there was no improvement with treatment in vitamin D-deficient animals.…”

“…Vitamin D has been shown to downregulate the expression of inducible nitric oxide synthesis (iNOS) (Garcion et al, 1998) and to regulate the expression of gamma glutamyl transpeptidase (Garcion et al, 1999), an enzyme important in the glutathione pathway; these findings suggest that vitamin D has an important role in antioxidant metabolism. Vitamin D-deficient aged (22-month-old) male Fischer 344 rats have elevated inflammatory proteins in the brain, including TNFα and IL-6, indicating that baseline brain inflammation may be increased even without injury (Cekic et al, 2011). Furthermore, in middleaged (9-11-month-old) female Sprague-Dawley rats, a vitamin D-deficient diet produced elevated IL-6 levels within the brain and reduced insulin-like growth factor 1 (IGF-1) levels within plasma and brain following ischemia (Balden et al, 2012).…”

“…Although progesterone, a neurosteroid that has been beneficial as a treatment in traumatic brain injury in recent clinical trials (Wright et al, 2007;Xiao et al, 2008), was beneficial in injured control animals, there was no improvement with treatment in vitamin D-deficient animals. This suggests that vitamin D deficiency exacerbates traumatic brain injury and diminishes the benefits of progesterone treatment (Cekic et al, 2011).…”