Mi-Mi Tang

The impacts of swimming exercise on hippocampal expression of neurotrophic factors in rats exposed to chronic unpredictable mild stress.

Depression is associated with stress-induced neural atrophy in limbic brain regions, whereas exercise has antidepressant effects as well as increasing hippocampal synaptic plasticity by strengthening neurogenesis, metabolism, and vascular function. A key mechanism mediating these broad benefits of exercise on the brain is induction of neurotrophic factors, which instruct downstream structural and functional changes. To systematically evaluate the potential neurotrophic factors that were involved in the antidepressive effects of exercise, in this study, we assessed the effects of swimming exercise on hippocampal mRNA expression of several classes of the growth factors (BDNF, GDNF, NGF, NT-3, FGF2, VEGF, and IGF-1) and peptides (VGF and NPY) in rats exposed to chronic unpredictable mild stress (CUMS). Our study demonstrated that the swimming training paradigm significantly induced the expression of BDNF and BDNF-regulated peptides (VGF and NPY) and restored their stress-induced downregulation. Additionally, the exercise protocol also increased the antiapoptotic Bcl-xl expression and normalized the CUMS mediated induction of proapoptotic Bax mRNA level. Overall, our data suggest that swimming exercise has antidepressant effects, increasing the resistance to the neural damage caused by CUMS, and both BDNF and its downstream neurotrophic peptides may exert a major function in the exercise related adaptive processes to CUMS.

Neurochemical effects of chronic administration of calcitriol in rats.

Despite accumulating data showing the various neurological actions of vitamin D (VD), its effects on brain neurochemistry are still far from fully understood. To further investigate the neurochemical influence of VD, we assessed neurotransmitter systems in the brain of rats following 6-week calcitriol (1,25-dihydroxyvitamin D) administration (50 ng/kg/day or 100 ng/kg/day). Both the two doses of calcitriol enhanced VDR protein level without affecting serum calcium and phosphate status. Rats treated with calcitriol, especially with the higher dose, exhibited elevated γ-aminobutyric acid (GABA) status. Correspondingly, the mRNA expression of glutamate decarboxylase (GAD) 67 was increased. 100 ng/kg of calcitriol administration also increased glutamate and glutamine levels in the prefrontal cortex, but did not alter glutamine synthetase (GS) expression. Additionally, calcitriol treatment promoted tyrosine hydroxylase (TH) and tryptophan hydroxylase 2 (TPH2) expression without changing dopamine and serotonin status. However, the concentrations of the metabolites of dopamine and serotonin were increased and the drug use also resulted in a significant rise of monoamine oxidase A (MAOA) expression, which might be responsible to maintain the homeostasis of dopaminergic and serotonergic neurotransmission. Collectively, the present study firstly showed the effects of calcitriol in the major neurotransmitter systems, providing new evidence for the role of VD in brain function.

Antidepressant-like effect of n-3 PUFAs in CUMS rats: role of tPA/PAI-1 system

BDNF is strongly implicated in the development of depression. Recent evidence has indicated that tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) are related to the cleavage of pro-brain-derived neurotrophic factor (BDNF) into its mature form. Chronic unpredicted mild stress (CUMS) is widely used to induce depressive behaviors in rodents. Therefore, we investigated the effects of PUFAs and sertraline on tPA/PAI-1 system in CUMS rats. After 5 weeks of CUMS procedures, the rats were induced to a depressive-like state. The expressions of PAI-1 and proBDNF were increased in the prefrontal cortex and hippocampus of CUMS rats. N-3 polyunsaturated fatty acids (PUFAs) or sertraline administration reversed the changes in behavioral test and induced the expression of tPA in certain brain areas, but failed to restore the CUMS-induced PAI-1 expression. Meanwhile, the antidepressant treatment also accelerated the extracellular conversion of proBDNF into mature BDNF in CUMS rats. Our results firstly showed the synchronously altered balance of tPA/PAI-1 system in the prefrontal cortex and hippocampus of CUMS rats, which was partly ameliorated by PUFAs and sertraline medication, providing new evidence for the involvement of tPA/PAI-1 system in the progression and treatment of depression.

Long Chain Omega-3 Polyunsaturated Fatty Acid Supplementation Alleviates Doxorubicin-Induced Depressive-Like Behaviors and Neurotoxicity in Rats: Involvement of Oxidative Stress and Neuroinflammation

Doxorubicin (DOX) is a chemotherapeutic agent widely used in human malignancies. Its long-term use can cause neurobiological side-effects associated with depression. Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), the essential fatty acids found in fish oil, possess neuroprotecitve and antidepressant activities. Thus, the aim of this study was to explore the potential protective effects of ω-3 PUFAs against DOX-induced behavioral changes and neurotoxicity. ω-3 PUFAs were given daily by gavage (1.5 g/kg) over three weeks starting seven days before DOX administration (2.5 mg/kg). Open-field test (OFT) and forced swimming test (FST) were conducted to assess exploratory activity and despair behavior, respectively. Our data showed that ω-3 PUFAs supplementation significantly mitigated the behavioral changes induced by DOX. ω-3 PUFAs pretreatment also alleviated the DOX-induced neural apoptosis. Meanwhile, ω-3 PUFAs treatment ameliorated DOX-induced oxidative stress in the prefrontal cortex and hippocampus. Additionally, gene expression of pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α, and the protein levels of NF-κB and iNOS were significantly increased in brain tissues of DOX-treated group, whereas ω-3 PUFAs supplementation significantly attenuated DOX-induced neuroinflammation. In conclusion, ω-3 PUFAs can effectively protect against DOX-induced depressive-like behaviors, and the mechanisms underlying the neuroprotective effect are potentially associated with its anti-oxidant, anti-inflammatory, and anti-apoptotic properties.

Maternal diet of polyunsaturated fatty acid altered the cell proliferation in the dentate gyrus of hippocampus and influenced glutamatergic and serotoninergic systems of neonatal female rats.

BackgroundLong-chain polyunsaturated fatty acids (PUFAs) are major components of the phospholipids that forming the cell membrane. Insufficient availability of PUFAs during prenatal period decreases accretion of docosahexaenoic acid (DHA) in the developing brain. DHA deficiency is associated with impaired attention and cognition, and would precipitate psychiatric symptoms. However, clinical studies on the potential benefits of dietary DHA supplementation to neural development have yielded conflicting results.MethodsTo further investigate the neurochemical influence of maternal PUFAs levels, we assessed the functioning of various neurotransmitter systems including glutamatergic, dopaminergic, norepinephrinergic and serotoninergic systems in the brain of neonatal female rats by HPLC-MS/MS. Meanwhile, the cell proliferation of neonatal rats was investigated using immunefluorescence.ResultsDifferent maternal n-3 PUFAs dietary influenced the FA composition, cell proliferation in the dentate gyrus of hippocampus and the contents of γ-aminobutyric acid (GABA), glutamine (GLN), dopamine (DA) and its metabolites [3,4- dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA)], norepinephrine (NE), vanilmandelic acid (VMA) and 5-HT turnover in the brain of neonatal rats. However, the mRNA expression of key synthase of neurotransmitters remains stable.ConclusionsOur study showed that maternal deficiency of n-3 PUFAs might play an important role in central nervous system of neonatal female rats mainly through impairing the normal neurogenesis and influencing glutamatergic system and 5-HT turnover.

Association between Vitamin D Receptor Gene Polymorphisms with Childhood Temporal Lobe Epilepsy

Vitamin D (VD) is implicated in multiple aspects of human physiology and vitamin D receptor (VDR) polymorphisms are associated with a variety of neuropsychiatric disorders. Although VD deficiency is highly prevalent in epilepsy patients and converging evidence indicates a role for VD in the development of epilepsy, no data is available on the possible relationship between epilepsy and genetic variations of VDR. In this study, 150 controls and 82 patients with temporal lobe epilepsy (TLE) were genotyped for five common VDR polymorphisms (Cdx-2, FokI, BsmI, ApaI and TaqI) by the polymerase chain reaction-ligase detection reaction method. Our results revealed that the frequency of FokI AC genotype was significantly higher in the control group than in the patients (p = 0.003, OR = 0.39, 95% CI = 0.21–0.73), whereas the AA genotype of ApaI SNP was more frequent in patients than in controls (p = 0.018, OR = 2.92, 95% CI = 1.2–7.1). However, no statistically significant association was found between Cdx-2, BsmI and TaqI polymorphisms and epilepsy. Additionally, in haplotype analysis, we found the haplotype GAT (BsmI/ApaI/TaqI) conferred significantly increased risk for developing TLE (p = 0.039, OR = 1.62, 95% CI = 1.02–2.56). As far as we know, these results firstly underline the importance of VDR polymorphisms for the genetic susceptibility to epilepsy.

Effects of repeated administration of rifampicin and isoniazid on vitamin D metabolism in mice.

Vitamin D deficiency is prevalent in tuberculosis (TB) patients and the anti-TB drugs, especially rifampicin (RIF) and isoniazid (INH), are associated with altered endocrine actions of vitamin D. Although it is well-known that these two drugs can affect a variety of cytochrome P450 (CYP450) activity, their influence on the CYP450 enzymes involved in vitamin D metabolism remains largely unknown. To fill this critical gap, serum vitamin D status and the expression of hepatic CYP2R1 and CYP27A1 and renal CYP27B1 and CYP24A1 were assessed in mice following 3-week exposure to 100 mg/kg/day RIF or (and) 50 mg/kg/day INH. Unexpectedly, we found either RIF or co-treatment the two drugs increased the concentrations of 25-hydroxyvitamin D3 (25(OH)D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3), without affecting 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) status. In parallel, enhanced hepatic expressions of 25-hydroxylase enzymes, CYP2R1 and (or) CYP27A1, were found in RIF and RIF+INH groups. However, co-administration of RIF and INH inhibited the expression of CYP27B1, while inducing CYP24A1 expression. Collectively, our data firstly showed that RIF and co-treatment of RIF and INH can both enhance 25-hydroxylation and 24-hydroxylation of vitamin D, providing novel evidence for the involvement of anti-TB drugs in the metabolism of vitamin D.

Chronic stress causes neuroendocrine-immune disturbances without affecting renal vitamin D metabolism in rats

IntroductionVitamin D (VD) insufficiency has been repeatedly observed in the medical conditions associated with inflammation, such as cardiovascular disease, diabetes and depression. However, contrasting to the observational evidence, randomized trials of VD supplementation failed to demonstrate such link. Given the recent evidence that the inflammatory process can in turn alter VD metabolism, it has been hypothesized that the insufficient VD status could be the result rather than the cause of chronic inflammation involved in the onset of depression and other disease conditions.Materials and methodsChronic mild stress (CMS) is a valid animal model of depression that accompanied with neuroendocrine-immune disturbances. In the present research, we assessed serum VD concentrations and renal expression of the cytochromes P450 enzymes involved in VD activation (CYP27B1) and catabolism (CYP24A1) of rats following 8-week exposure to CMS.ResultsWhile CMS induced the rats to a depression-like state and increased serum levels of the proinflammatory cytokines and corticosterone, and the antidepressant, sertraline, mitigated depression-like behaviors and neuroendocrine-immune disturbances, neither the stress regimen nor sertraline significantly affected endocrine metabolism of VD.ConclusionOur data suggest that the stress-induced neuroendocrine-immune disturbances may account for the development of depression, but are not responsible for the insufficient VD status that frequently observed in depressed patients.

Effect of Antiepileptic Therapy on Serum 25(OH)D3 and 24,25(OH)2D3 Levels in Epileptic Children.

Background: Vitamin D deficiency is not only associated with the adverse effects of chronic treatment with antiepileptic drugs (AEDs), but also with epilepsy. Although emerging evidence suggests that AEDs can accelerate the vitamin D catabolism, resulting in suboptimal vitamin D status, there are a limited number of studies examining the vitamin D status in epileptic patients, especially in first-episode or AEDs-naïve children. Methods: Determined with high-performance liquid chromatography-tandem mass spectrometry, circulating 25(OH)D₃ and 24,25(OH)₂D₃ levels, and 24,25(OH)₂D₃:25(OH)D₃ ratio were compared between AEDs-treated epileptic (n = 363) and control (n = 159) children. To further figure out whether the patients were in a vitamin D deficient prone state even before treatment, epileptic children before their initiation of treatment (n = 51) were enrolled into a follow-up study. Results: A significant decrease of 25(OH)D₃ and 24,25(OH)₂D₃ levels, but a significant increase of 24,25(OH)₂D₃:25(OH)D₃ ratio was observed in epileptic children, compared with controls. Baseline 25(OH)D₃, 24,25(OH)₂D₃ and 24,25(OH)₂D₃:25(OH)D₃ ratio in the follow-up group were similar to those in controls, but significantly changed with 2 months of AED therapy. Conclusions: Disturbed vitamin D levels were possibly the consequence of AED therapy, rather than the contributing factor of epilepsy. Collectively, circulating vitamin D levels should be monitored and corrected in AEDs-treated epileptic children.

Simultaneous Quantification of 25-Hydroxyvitamin D3 and 24,25-Dihydroxyvitamin D3 in Rats Shows Strong Correlations between Serum and Brain Tissue Levels

While vitamin D3 is recognized as a neuroactive steroid affecting both brain development and function, efficient analytical method in determining vitamin D3 metabolites in the brain tissue is still lacking, and the relationship of vitamin D3 status between serum and brain remains elusive. Therefore, we developed a novel analysis method by using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to simultaneously quantify the concentrations of 25-hydroxyvitamin D3 (25(OH)D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) in the serum and brain of rats fed with different dose of vitamin D3. We further investigated whether variations of serum vitamin D3 metabolites could affect vitamin D3 metabolite levels in the brain. Serum and brain tissue were analyzed by HPLC-MS/MS with electrospray ionization following derivatization with 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD). The method is highly sensitive, specific, and accurate to quantify 25(OH)D3 and 24,25(OH)2D3 in animal brain tissue. Vitamin D3 metabolites in brain tissue were significantly lower in rats fed with a vitamin D deficiency diet than in rats fed with high vitamin D3 diet. There was also a strong correlation of vitamin D3 metabolites in serum and brain. These results indicate that vitamin D3 status in serum affects bioavailability of vitamin D3 metabolites in the brain.