Brain vitamin D3-auto/paracrine system in relation to structural, neurophysiological, and behavioral disturbances associated with glucocorticoid-induced neurotoxicity

Abstract

IntroductionVitamin D3 (VD3) is a potent para/autocrine regulator and neurosteroid that can strongly influence nerve cell function and counteract the negative effects of glucocorticoid (GC) therapy. The aim of the study was to reveal the relationship between VD3 status and behavioral, structural-functional and molecular changes associated with GC-induced neurotoxicity.MethodsFemale Wistar rats received synthetic GC prednisolone (5 mg/kg b.w.) with or without VD3 (1000 IU/kg b.w.) for 30 days. Behavioral, histological, physiological, biochemical, molecular biological (RT-PCR, Western blotting) methods, and ELISA were used.Results and discussionThere was no difference in open field test (OFT), while forced swim test (FST) showed an increase in immobility time and a decrease in active behavior in prednisolone-treated rats, indicative of depressive changes. GC increased the perikaryon area, enlarged the size of the nuclei, and caused a slight reduction of cell density in CA1-CA3 hippocampal sections. We established a GC-induced decrease in the long-term potentiation (LTP) in CA1-CA3 hippocampal synapses, the amplitude of high K+-stimulated exocytosis, and the rate of Ca2+-dependent fusion of synaptic vesicles with synaptic plasma membranes. These changes were accompanied by an increase in nitration and poly(ADP)-ribosylation of cerebral proteins, suggesting the development of oxidative-nitrosative stress. Prednisolone upregulated the expression and phosphorylation of NF-κB p65 subunit at Ser311, whereas downregulating IκB. GC loading depleted the circulating pool of 25OHD3 in serum and CSF, elevated VDR mRNA and protein levels but had an inhibitory effect on CYP24A1 and VDBP expression. Vitamin D3 supplementation had an antidepressant-like effect, decreasing the immobility time and stimulating active behavior. VD3 caused a decrease in the size of the perikaryon and nucleus in CA1 hippocampal area. We found a recovery in depolarization-induced fusion of synaptic vesicles and long-term synaptic plasticity after VD3 treatment. VD3 diminished the intensity of oxidative-nitrosative stress, and suppressed the NF-κB activation. Its ameliorative effect on GC-induced neuroanatomical and behavioral abnormalities was accompanied by the 25OHD3 repletion and partial restoration of the VD3-auto/paracrine system.ConclusionGC-induced neurotoxicity and behavioral disturbances are associated with increased oxidative-nitrosative stress and impairments of VD3 metabolism. Thus, VD3 can be effective in preventing structural and functional abnormalities in the brain and behavior changes caused by long-term GC administration.

Vitamin D3 Affects Glucocorticoid-Sensitive Receptors and Brain-Derived Neurotrophic Factor in Prednisolone-Induced Neurotoxicity

“…Given th e close association between GC and BDNF signaling, we next examined GC-induced alterations of brain BDNF expression. Our data indicate that long-term exposure of rats to prednisolone resulted in a marked (42%) increase in brain BDNF protein level compared to control, Table . Taken together, these findings suggest that BDNF might be involved in initial stress response, playing a compensatory role by preventing oxidative damage to cell structures and low-grade inflammation as well as depressive-like behavior identified in our previous work [3]. We demonstrated the ability of D 3 to partially normalize brain BDNF protein levels compared to prednisolonetreated animals.…”

“…Various sources of evidence indicate that GCs and their receptors interact with one of the major neurotrophins in the CNS, the brain-derived neurotrophic factor (BDNF), influ encing important aspects of neurona l cell physiology such as cell viability, memory formation, behavioral responses, and adaptation to stressful stimuli [2]. In addition, vitamin D 3 (D 3 ) deficiency and impaired signaling via D 3 re ceptor (VDR) were previously reported to be essential contributing factors in the development of GC-induced adversary effects in the CNS [3]. However, the molecular mechanisms of D 3 involvement in the regulation of steroid receptors interplay and BDNF expression have not been sufficiently studied.Aim.…”

Investigating the Impact of Selective Modulators on the Renin–Angiotensin–Aldosterone System: Unraveling Their Off-Target Perturbations of Transmembrane Ionic Currents

“…However, during severe injuries, the daily production rate of glucocorticoids can significantly increase, up to at least tenfold. Additionally, previous research has indicated that locally produced steroids in the brain and endocrine glands, known as neurosteroids, may play a role in regulating cell excitability [ 40 , 41 , 42 ]. The DEX suppression test has been widely used to screen for adrenal hyperfunction because it is a potent synthetic glucocorticoid.…”