Brain-derived Neurotrophic Factor Protein Levels Research Articles

The microRNA-195 - BDNF pathway and cognitive deficits in schizophrenia patients with minimal antipsychotic medication exposure

Cognitive impairment is a core characteristic of schizophrenia, but its underlying neural mechanisms remain poorly understood. Reduced brain-derived neurotrophic factor (BDNF), a protein critical for neural plasticity and synaptic signaling, is one of the few molecules consistently associated with cognitive deficits in schizophrenia although the etiological pathway leading to BDNF reduction in schizophrenia is unclear. We examined microRNA-195 (miR-195), a known modulator of BDNF protein expression, as a potential mechanistic component. One-hundred and eighteen first-episode patients with schizophrenia either antipsychotic medication-naïve or within two weeks of antipsychotic medication exposure and forty-seven age- and sex-matched healthy controls were enrolled. MiR-195 and BDNF mRNA and BDNF protein levels in peripheral blood were tested. Cognitive function was assessed using the MATRICS Consensus Cognitive Battery (MCCB). MiR-195 was significantly higher (p = 0.01) whereas BDNF mRNA (p < 0.001) and protein (p = 0.016) levels were significantly lower in patients compared with controls. Higher miR-195 expression was significantly correlated to lower BDNF protein levels in patients (partial r = −0.28, p = 0.003) and lower BDNF protein levels were significantly associated with poorer overall cognitive performance by MCCB and also in speed of processing, working memory, and attention/vigilance domains composite score (p = 0.002–0.004). The subgroup of patients with high miR-195 and low BDNF protein showed the lowest level of cognitive functions, and miR-195 showed significant mediation effects on cognitive functions through BDNF protein. Elevated miR-195 may play a role in regulating BDNF protein expression thereby influencing cognitive impairments in schizophrenia, suggesting that development of cognition enhancing treatment for schizophrenia may consider a micro-RNA based strategy.

Ninjin'yoeito Alleviates Neuropathic Pain Induced by Chronic Constriction Injury in Rats.

Kampo medicines are frequently used empirically to treat pain in clinical practice. Ninjin'yoeito (NYT), which is associated with few adverse effects, is often used to treat the elderly, but has not yet been examined in detail. We herein investigated the effects of NYT, at 500 and 1,000 mg/kg p.o. (NYT500/NYT1000 group) in single and repeated administrations for 14 days, on pain in rats with peripheral neuropathy induced by loose ligation of the sciatic nerve (chronic constriction injury: CCI). Untreated CCI rats given distilled water were used as a control group. To assess induced pain, the pain threshold was measured using the von Frey test. To evaluate spontaneous pain, the ground-contact area of the paw with neuropathic pain was measured using the Dynamic Weight Bearing test. Serum samples were collected after the test to elucidate the mechanism of action of NYT, and brain-derived neurotrophic factor (BDNF) and corticosterone protein levels, which have been reported to change due to chronic pain, were analyzed. After single administration of NYT, the pain threshold rose in the NYT500 and NYT1000 groups. The pain threshold tended to rise on day 14 of repeated administration in the NYT500 group (p = 0.08) and it significantly rose at NYT1000 group (p < 0.05) compared to Control group. In addition, the foot contact area increased (p = 0.09). Therefore, CCI-induced pain was significantly remitted and spontaneous pain was remitted after repeated administration of NYT. Serum BDNF levels were higher in untreated CCI rats than in normal rats (p = 0.05), but decreased after the repeated administration of NYT (NYT1000, p = 0.15), while serum corticosterone levels were lower (p = 0.12) than those in normal rats and increased after the repeated administration of NYT (NYT1000, p = 0.07). The blood BDNF level has been suggested to influence pain intensity. The findings demonstrated NYT effectively treats neuropathic pain, suggesting that a NYT-induced decrease in blood BDNF contributed to the mechanism of pain relief. In addition, the variation of corticosterone was observed, suggesting that normalization of responsiveness to stress by NYT contributed to the pain relief.

Cinnamomum zeylanicum extract has antidepressant-like effects by increasing brain-derived neurotrophic factor (BDNF) and its receptor in prefrontal cortex of rats.

Depression is one of the most common mood disorders. Considering the evidence on the effect of Cinnamomum on mood disorders, this study investigatedthe effect of hydroalcoholic extract of Cinnamomum (HEC) in an animal model of depression. Thirty-two male rats were selected and divided into four groups (n=8) including: control, depressed, and depressed treated with200 and 400 mg/kg HEC. Depression induction protocol was conducted in all groups except for the control group. Sucrose preference test (SPT) and forced swimming test (FST) were done to analyze the depression score. After four weeks, the animals brain cortex was removed and BDNF protein and tyrosine receptor kinase B (TrkB) gene expression levels were determined by ELISA and Real Time PCR, respectively. The results of this study showed that 400 mg/kg of HEC increased the tendency to drink the sucrose solution. Furthermore, immobility time significantly increased in the depressed group compared to the control group while it was attenuated by administration of 400 mg/kg extract on the 28th day versus the depressed group. Also the extract at both doses increased swimming time compared to the depressed group. In addition, an increase in the BDNF protein and TrkB gene expression levels was observed in the prefrontal cortex of the treatment groups. We found that HEC ameliorated depression symptoms in rats and these effects were probably due to an increase in BDNF proteins and its receptor, TrkB, gene expressions in the prefrontal cortex.

The Role of Brain-Derived Neurotrophic Factor in Irritable Bowel Syndrome.

Several studies have implied a role of brain-derived neurotrophic factor (BDNF) in abdominal pain modulation in irritable bowel syndrome (IBS). The aim of this study was to establish BDNF protein expression in human colonic biopsies and to show variation in IBS compared to controls. BDNF protein and mRNA levels were correlated with IBS symptom severity based on the IBS-symptom severity score (IBS-SSS). Biopsies from the descending colon and IBS-SSS were obtained from 10 controls and 20 IBS patients. Total protein of biopsies was extracted and assessed by ELISA and Western Blot. Total mRNA was extracted and gene expression measured by nCounter analysis. In IBS patients, symptom severity scores ranged from 124 to 486 (mean ± sem: 314.2 ± 21.2, >300 represents severe IBS) while controls ranged from 0 to 72 (mean ± sem: 27.7 ± 9.0, <75 represents healthy subjects, p < 0.001). IBS patients reported significantly more food malabsorption, former abdominal surgery and psychiatric comorbidities. BDNF protein was present in all samples and did not differ between IBS and controls or sex. Subgroup analysis showed that female IBS patients expressed significantly more BDNF mRNA compared to male patients (p < 0.05) and male IBS-D patients had higher IBS symptom severity scores and lower BDNF mRNA and protein levels compared to male controls (p < 0.05). Scatter plot showed a significant negative correlation between IBS-SSS and BDNF mRNA levels in the cohort of male IBS-D patients and their male controls (p < 0.05). We detected a high proportion of gastrointestinal surgery in IBS patients and confirmed food intolerances and psychiatric diseases as common comorbidities. Although in a small sample, we demonstrated that BDNF is detectable in human descending colon, with higher BDNF mRNA levels in female IBS patients compared to males and lower mRNA and protein levels in male IBS-D patients compared to male controls. Further research should be directed toward subgroups of IBS since their etiologies might be different.

ERRγ ligand HPB2 upregulates BDNF-TrkB and enhances dopaminergic neuronal phenotype

Brain derived neurotrophic factor (BDNF) promotes maturation of dopaminergic (DAergic) neurons in the midbrain and positively regulates their maintenance and outgrowth. Therefore, understanding the mechanisms regulating the BDNF signaling pathway in DAergic neurons may help discover potential therapeutic strategies for neuropsychological disorders associated with dysregulation of DAergic neurotransmission. Because estrogen‐related receptor gamma (ERRγ) is highly expressed in both the fetal nervous system and adult brains during DAergic neuronal differentiation, and it is involved in regulating the DAergic neuronal phenotype, we asked in this study whether ERRγ ligand regulates BDNF signaling and subsequent DAergic neuronal phenotype. Based on the X-ray crystal structures of the ligand binding domain of ERRγ, we designed and synthesized the ERRγ agonist, (E)-4-hydroxy-N'-(4-(phenylethynyl)benzylidene)benzohydrazide (HPB2) (Kd value, 8.35 μmol/L). HPB2 increased BDNF mRNA and protein levels, and enhanced the expression of the BDNF receptor tropomyosin receptor kinase B (TrkB) in human neuroblastoma SH-SY5Y, differentiated Lund human mesencephalic (LUHMES) cells, and primary ventral mesencephalic (VM) neurons. HPB2-induced upregulation of BDNF was attenuated by GSK5182, an antagonist of ERRγ, and siRNA-mediated ERRγ silencing. HPB2-induced activation of extracellular-signal-regulated kinase (ERK) and phosphorylation of cAMP-response element binding protein (CREB) was responsible for BDNF upregulation in SH-SY5Y cells. HPB2 enhanced the DAergic neuronal phenotype, namely upregulation of tyrosine hydroxylase (TH) and DA transporter (DAT) with neurite outgrowth, both in SH-SY5Y and primary VM neurons, which was interfered by the inhibition of BDNF-TrkB signaling, ERRγ knockdown, or blockade of ERK activation. HPB2 also upregulated BDNF and TH in the striatum and induced neurite elongation in the substantia nigra of mice brain. In conclusion, ERRγ activation regulated BDNF expression and the subsequent DAergic neuronal phenotype in neuronal cells. Our results might provide new insights into the mechanism underlying the regulation of BDNF expression, leading to novel therapeutic strategies for neuropsychological disorders associated with DAergic dysregulation.

Effects of scorpion venom heat-resistant peptide on the hippocampal neurons of kainic acid-induced epileptic rats.

Scorpion venom is a Chinese medicine for epilepsy treatment, but the underlying mechanism is not clear. Scorpion venom heat-resistant peptide (SVHRP), a peptide isolated from the venom of Buthus martensii Karsch, has an anti-epileptic effect by reducing seizure behavior according to a modified Racine scale. The present study aimed to investigate the molecular mechanism of SVHRP on temporal lobe epilepsy. The hippocampus and hippocampal neurons from kainic acid-induced epileptic rats were treated with SVHRP at different doses and duration. Quantitative RT-PCR and immunoblotting were used to detect the expression level of brain-derived neurotrophic factor (BDNF), neuropeptide Y (NPY), cAMP-response element binding protein (CREB), stromal interaction molecule (STIM), and calcium release-activated calcium channel protein 1 (ORAI1). In the hippocampal tissues and primary hippocampal neuron cultures, SVHRP treatment resulted in increased mRNA and protein levels of BDNF and NPY under the epileptic condition. The upregulation of BDNF and NPY expression was positively correlated with the dose level and treatment duration of SVHRP in hippocampal tissues from kainic acid-induced epileptic rats. On the other hand, no significant changes in the levels of CREB, STIM, or ORAI1 were observed. SVHRP may exhibit an anti-epileptic effect by upregulating the expression of BDNF and NPY in the epileptic hippocampus.

Brain-derived neurotrophic factor as a potential therapeutic tool in the treatment of nervous system disorders

Brain-derived neurotrophic factor (BDNF) plays an important role in the proper functioning of the nervous system. It regulates the growth and survival of nerve cells, and is crucial in processes related to the memory, learning and synaptic plasticity. Abnormalities related to the distribution and secretion of BDNF protein accompany many diseases of the nervous system, in the course of which a significant decrease in BDNF level in the brain is observed. Impairments of BDNF transport may occur, for example, in the event of a single nucleotide polymorphism in the Bdnf (Val66Met) coding gene or due to the dysfunctions of the proteins involved in intracellular transport, such as huntingtin (HTT), huntingtin-associated protein 1 (HAP1), carboxypeptidase E (CPE) or sortilin 1 (SORT1). One of the therapeutic goals in the treatment of diseases of the central nervous system may be the regulation of expression and secretion of BDNF protein by nerve cells. Potential therapeutic strategies are based on direct injection of the protein into the specific region of the brain, the use of viral vectors expressing the Bdnf gene, transplantation of BDNF-producing cells, the use of substances of natural origin that stimulate the cells of the central nervous system for BDNF production, or the use of molecules activating the main receptor for BDNF – tyrosine receptor kinase B (TrkB). In addition, an appropriate lifestyle that promotes physical activity helps to increase BDNF level in the body. This paper summarizes the current knowledge about the biological role of BDNF protein and proteins involved in intracellular transport of this neurotrophin. Moreover, it presents contemporary research trends to develop therapeutic methods, leading to an increase in the level of BDNF protein in the brain.

Continuous administration of a p38α inhibitor during the subacute phase after transient ischemia-induced stroke in the rat promotes dose-dependent functional recovery accompanied by increase in brain BDNF protein level.

There is unmet need for effective stroke therapies. Numerous neuroprotection attempts for acute cerebral ischemia have failed and as a result there is growing interest in developing therapies to promote functional recovery through increasing synaptic plasticity. For this research study, we hypothesized that in addition to its previously reported role in mediating cell death during the acute phase, the alpha isoform of p38 mitogen-activated protein kinase, p38α, may also contribute to interleukin-1β-mediated impairment of functional recovery during the subacute phase after acute ischemic stroke. Accordingly, an oral, brain-penetrant, small molecule p38α inhibitor, neflamapimod, was evaluated as a subacute phase stroke treatment to promote functional recovery. Neflamapimod administration to rats after transient middle cerebral artery occlusion at two dose levels was initiated outside of the previously characterized therapeutic window for neuroprotection of less than 24 hours for p38α inhibitors. Six-week administration of neflamapimod, starting at 48 hours after reperfusion, significantly improved behavioral outcomes assessed by the modified neurological severity score at Week 4 and at Week 6 post stroke in a dose-dependent manner. Neflamapimod demonstrated beneficial effects on additional measures of sensory and motor function. It also resulted in a dose-related increase in brain-derived neurotrophic factor (BDNF) protein levels, a previously reported potential marker of synaptic plasticity that was measured in brain homogenates at sacrifice. Taken together with literature evidence on the role of p38α-dependent suppression by interleukin-1β of BDNF-mediated synaptic plasticity and BDNF production, our findings support a mechanistic model in which inhibition of p38α promotes functional recovery after ischemic stroke by blocking the deleterious effects of interleukin-1β on synaptic plasticity. The dose-related in vivo efficacy of neflamapimod offers the possibility of having a therapy for stroke that could be initiated outside the short time window for neuroprotection and for improving recovery after a completed stroke.

Alterations in BDNF Protein Concentrations in the Hippocampus do not Explain the Pro-Neurogenic Effect of Citalopram on Adult Neurogenesis.

Brain-derived neurotrophic factor (BDNF) has been implicated in the pro-neurogenic effect of selective serotonin reuptake inhibitors. In this study, we used Tph2 -/- mice lacking brain serotonin to dissect the interplay between BDNF and the serotonin system in mediating the effects of antidepressant pharmacotherapy on adult neurogenesis in the hippocampus. Besides citalopram (CIT), we tested tianeptine (TIA), an antidepressant whose mechanism of action is not well understood. Specifically, we examined cell survival and endogenous concentrations of BDNF following daily injection of the drugs. Twenty-one days of CIT, but not of TIA, led to a significant increase in the survival of newly generated cells in the dentate gyrus of wild-type mice, without a significant effect on BDNF protein levels by either treatment. In Tph2 -/- mice, adult neurogenesis was consistently increased. Furthermore, Tph2 -/- mice showed increased BDNF protein levels, which were not affected by TIA but were significantly reduced by CIT. We conclude that the effects of CIT on adult neurogenesis are not explained by changes in BDNF protein concentrations in the hippocampus.

Nicotine induces P2X4 receptor, interleukin-1 beta, and brain-derived neurotrophic factor expression in BV2 microglia cells.

Upregulation of P2X4 receptor (P2X4R), brain-derived neurotrophic factor (BDNF), and interleukin-1 beta (IL-1β) in activated microglia is associated with hyperalgesia. This study investigated whether nicotine increases pain hypersensitivity by altering the expression of these molecules in microglia. We also examined the role of interferon regulatory factor 8 (IRF8) in this process. Experiments were performed in BV2 microglial cells. IRF8 was knocked down or overexpressed using lentiviruses harboring a short hairpin RNA targeting IRF8 or an IRF8 overexpression construct, respectively. P2X4R, BDNF, and IL-1β mRNA and protein levels were evaluated by real-time PCR and western blotting, respectively, and BDNF and IL-1β secretion was assessed by ELISA. Chronic nicotine exposure enhanced the expression of P2X4R, BDNF, and IL-1β in BV2 cells, and stimulated the release of BDNF and IL-1β in the presence of ATP. IRF8 was found to mediate the nicotine-induced increases in BDNF and IL-1β mRNA and P2X4R protein levels in BV2 cells. Nicotine may increase pain hypersensitivity by promoting the expression of P2X4R, BDNF, and IL-1β through modulation of IRF8 levels in microglial cells.

Rottlerin, BDNF, and the impairment of inhibitory avoidance memory.

As a eukaryotic elongation factor 2 kinase (eEF2K) inhibitor and a mitochondrial uncoupler, oncologists have extensively studied rottlerin. Neuroscientists, however, have accumulated scarce data on the role of rottlerin in affective and cognitive functions. Only two prior studies have, respectively, documented its antidepressant-like effect and how it impairs psychostimulant-supported memory. Whether or not rottlerin would affect aversive memory remains unknown. Hence, we sought to investigate the effects of rottlerin on aversive memory in the inhibitory avoidance (IA) task in mice. Male C57BL/6J mice were trained to acquire the IA task. Rottlerin (5 mg/kg, i.p. or 3 μg bilaterally in the hippocampus) or the vehicle was administered before footshock training (acquisition), after footshock training (consolidation), after the memory reactivation (reconsolidation), and before the test (retrieval) in the IA task. Systemic and intrahippocampal rottlerin impaired the acquisition, consolidation, and retrieval of IA memory, without affecting the reconsolidation process. Rottlerin (5 mg/kg, i.p.) induced a fast-onset and long-lasting increase in the brain-derived neurotrophic factor (BDNF) protein levels in the mouse hippocampus. Systemic injection of 7,8-dihydroxyflavone (7,8-DHF, 30 mg/kg), a BDNF tropomyosin receptor kinase B (TrkB) agonist impaired IA memory consolidation, and treatment with K252a (5 μg/kg), a Trk receptor antagonist, reversed the suppressing effect of rottlerin on IA memory consolidation. Rottlerin impairs IA memory consolidation through the enhancement of BDNF signaling in the mouse hippocampus. Excessive brain BDNF levels can be detrimental to cognitive function. Rottlerin is likely to affect the original memory-associated neuroplasticity. Thus, it can be combined with exposure therapy to facilitate the forgetting of maladaptive aversive memory, such as post-traumatic stress disorder (PTSD).

The dopaminergic alterations induced by 4-F-PCP and 4-Keto-PCP may enhance their drug-induced rewarding and reinforcing effects: Implications for abuse.

Novel psychoactive substances remain the popular recreational drugs of use over the years. They continue to bypass government restrictions due to their synthesis and modifications. Recent additions to the lists are the 4-F-PCP and 4-Keto-PCP, analogs of the drug phencyclidine (PCP) known to induce adverse effects and abuse potential. However, studies on the abuse potential of 4-F-PCP and 4-Keto-PCP remain scarce. The rewarding and reinforcing effects of the drugs were assessed using conditioned place preference (CPP), self-administration, and locomotor sensitization tests. Dopamine (DA) receptor antagonists (SCH23390 and haloperidol) were administered during CPP to evaluate the involvement of the mesolimbic dopaminergic system. DA-related protein expression in the nucleus accumbens (NAcc) and ventral tegmental area (VTA) was measured. Additionally, phosphorylated cyclic-adenosine monophosphate-activated protein (AMP) response element-binding (p-CREB) protein, deltaFosB (∆FosB), and brain-derived neurotrophic factor (BDNF) protein levels in the NAcc were measured to assess the addiction neural plasticity effect of the drugs. Both 4-F-PCP and 4-Keto-PCP-induced CPP and self-administration; however, only 4-F-PCP elicited locomotor sensitization. Treatment with DA receptor antagonists (SH23390 and haloperidol) inhibited the 4-F- and 4-Keto-induced CPP. Both substances altered the levels of DA receptor D1 (DRD1), thyroxine hydroxylase (TH), DA receptor D2 (DRD2), p-CREB, ∆FosB, and BDNF. The results suggest that 4-F-PCP and 4-Keto-PCP may induce abuse potential in rodents via alterations in dopaminergic system accompanied by addiction neural plasticity.

The Chronic Treatment With 5-HT2A Receptor Agonists Affects the Behavior and the BDNF System in Mice.

Serotonin 5-HT2A receptors and the brain-derived neurotrophic factor (BDNF) are involved in the pathophysiology and treatment of many psychiatric diseases. However, the interaction between 5-HT2A and BDNF is still poorly understood. In the present paper, the effects of chronic treatment with mixed 5-HT2A/2C receptor agonist DOI, highly selective 5-HT2A agonists TCB-2 and 25CN-NBOH on behavior and the BDNF system have been investigated. Chronic treatment of males of C57Bl/6 mice with DOI, TCB-2 and 25CN-NBOH (1 mg/kg, i.p., 14 days) resulted in desensitization of 5-HT2A receptors. Treatment with 25CN-NBOH significantly increased startle amplitude. At the same time all used drugs failed to affect anxiety, exploratory and stereotyped behavior as well as spatial memory and learning. TCB-2 and 25CN-NBOH increased the BDNF mRNA level. All 5-HT2A agonists increased the proBDNF level but failed to alter the mature BDNF protein level. TrkB and p75NTR mRNA levels were affected by all utilized agonists. All drugs decreased the total level as well as membrane TrkB protein one indicating downregulation of TrkB receptors. All agonists decreased the membrane p75NTR protein level. Thus, we have shown for the first time that the chronic activation of the 5-HT2A receptor with agonists has affected the BDNF system almost on all levels-transcription, proBDNF production, TrkB and p75NTR receptors' level. The obtained data suggested possible suppression in BDNF-TrkB signaling under chronic treatment with 5-HT2A agonists.

Epigenetic perspective on the role of brain-derived neurotrophic factor in burnout

Brain-derived neurotrophic factor (BDNF) plays a potential role in the neurobiology of burnout, but there are no studies investigating the underlying genetic and epigenetic mechanisms. Our aim is to further explore the role of BDNF in burnout, by focusing on the Val66Met polymorphism and methylation patterns of the BDNF gene and serum BDNF (sBDNF) protein expression. We conducted a cross-sectional study by recruiting 129 individuals (59 with burnout and 70 healthy controls). Participants underwent a clinical interview, psychological assessment and blood sample collection. Polymorphism and DNA methylation were measured on DNA from whole blood, using pyrosequencing and sBDNF levels were measured using ELISA. We found significantly increased methylation of promoter I and IV in the burnout group, which also correlated with burnout symptoms. In addition, DNA methylation of promoter I had a significant negative effect on sBDNF. For DNA methylation of exon IX, we did not find a significant difference between the groups, nor associations with sBDNF. The Val66Met polymorphism neither differed between groups, nor was it associated with sBDNF levels. Finally, we did not observe differences in sBDNF level between the groups. Interestingly, we observed a significant negative association between depressive symptoms and sBDNF levels. The current study is the first to show that BDNF DNA methylation changes might play an important role in downregulation of the BDNF protein levels in burnout. The presence of depressive symptoms might have an additional impact on these changes.

DNA Methylation and Brain-Derived Neurotrophic Factor Expression Account for Symptoms and Widespread Hyperalgesia in Patients With Chronic Fatigue Syndrome and Comorbid Fibromyalgia.

The epigenetics of neurotrophic factors holds the potential to unravel the mechanisms underlying the pathophysiology of complex conditions such as chronic fatigue syndrome (CFS). This study was undertaken to explore the role of brain-derived neurotrophic factor (BDNF) genetics, epigenetics, and protein expression in patients with both CFS and comorbid fibromyalgia (CFS/FM). A repeated-measures study was conducted in 54 participants (28 patients with CFS/FM and 26 matched healthy controls). Participants underwent a comprehensive assessment, including questionnaires, sensory testing, and blood withdrawal. Serum BDNF (sBDNF) protein levels were measured using enzyme-linked immunosorbent assay, while polymorphism and DNA methylation were measured in blood using pyrosequencing technology. To assess the temporal stability of the measures, participants underwent the same assessment twice within 4 days. Repeated-measures mixed linear models were used for between-group analysis, with mean differences and 95% confidence intervals (95% CIs) shown. Compared to controls, serum BNDF was higher in patients with CFS/FM (F = 15.703; mean difference 3.31 ng/ml [95% CI 1.65, 4.96]; P = 0.001), whereas BDNF DNA methylation in exon 9 was lower (F = 7.543; mean difference -2.16% [95% CI -3.93, -0.83]; P = 0.007). BDNF DNA methylation was mediated by the Val66Met (rs6265) polymorphism. Lower methylation in the same region predicted higher sBDNF levels (F = 7.137, β = -0.408 [95% CI -0.711, -0.105]; P = 0.009), which in turn predicted participants' symptoms (F = 14.410, β = 3.747 [95% CI 1.79, 5.71]; P = 0.001) and widespread hyperalgesia (F = 4.147, β = 0.04 [95% CI 0.01, 0.08]; P = 0.044). Our findings indicate that sBDNF levels are elevated in patients with CFS/FM and that BDNF methylation in exon 9 accounts for the regulation of protein expression. Altered BDNF levels might represent a key mechanism explaining CFS/FM pathophysiology.

Hypertriglyceridemia-induced brain-derived neurotrophic factor in rat submandibular glands

ObjectivesSalivary glands produce brain-derived neurotrophic factor (BDNF), which increases plasma BDNF content. Salivary BDNF influences the hippocampus and enhances anxiety-like behaviors. Dyslipidemia affects the brain, promoting depression and anxiety-like behaviors. This study was performed to investigate whether hypertriglyceridemia influences salivary BDNF expression. MethodsHypertriglyceridemia was induced in rats by high-fat diet intake for 10 weeks. BDNF protein levels in the saliva and submandibular glands were measured using enzyme-linked immunosorbent assay (ELISA). Bdnf mRNA levels in the submandibular gland were determined using real-time polymerase chain reaction. ResultsA hypertriglyceridemia rat model was established. Body weight did not differ between the control and hypertriglyceridemia groups. Bdnf mRNA and protein expression was increased in the submandibular gland in the hypertriglyceridemia group compared to the control group. BDNF expression was also significantly increased in the saliva of the hypertriglyceridemia group. ConclusionsThis is first study to show that hypertriglyceridemia induces BDNF expression in the rat submandibular gland and suggests that salivary BDNF is associated with lipid metabolism.

Aerobic exercise delays retinal ganglion cell death after optic nerve injury

Aerobic exercise has been shown to play a crucial role in preventing neurological diseases and improving cognitive function. In the present study, we investigated the effect of treadmill training on retinal ganglion cells (RGCs) following optic nerve transection in adult rats. We exercised the rats on a treadmill for 5 d/week (30 min/d at a rate of 9 m/min) or placed control rats on static treadmills. After 3 weeks of exercise, the left optic nerve of each rat was transected. After the surgery, the rat was exercised for another week. The percentages of surviving RGCs in the axotomized eyes of inactive rats were 67% and 39% at 5 and 7 days postaxotomy, respectively. However, exercised rats had significant more RGCs at 5 (74% survival) and 7 days (48% survival) after axotomy. Moreover, retinal brain-derived neurotrophic factor (BDNF) protein levels were significantly upregulated in response to exercise compared with those in the axotomized eyes of inactive rats. Blocking BNDF signaling during exercise by intraperitoneal injections of ANA-12, a BDNF tropomyosin receptor kinase (TrkB) receptor antagonist, reduced the number of RGCs in exercised rats to the level of RGCs in the inactive rats, effectively abolishing the protection of RGCs afforded by exercise. The results suggest that treadmill training effectively rescues RGCs from neurodegeneration following optic nerve transection by upregulating the expression of BDNF.

Brain-Derived Neurotrophic Factor Inhibits the Wound-Healing and Cell Proliferative Ability of Human Airway Epithelial Cells in Asthmatic Children.

BackgroundAsthma is a chronic disease with high morbidity rates. Brain-derived neurotrophic factor (BDNF) has been proven to induce airway hyper-responsiveness, but the function of BDNF in the wound-healing process of asthmatic human airway epithelial cells (HAECs) remains unclear. This study investigated the effects of BDNF in asthmatic children with injured HAECs.Material/MethodsHAECs were obtained from healthy children and asthmatic children through bronchoscopy, and then cultured in air-liquid (ALI) interface with or without BDNF. A mechanical injury model was established for the wound-healing assay. Quantitative real-time polymerase chain reaction (qRT-PCR) assay was performed to measure BDNF mRNA expressions, while western blot assay was used for the measurement of BDNF and CCND1 protein expressions. Cell proliferation of impaired HAECs was assayed in a 3H-thymidine incorporation experiment.ResultsThe mRNA and protein levels of BDNF were overexpressed, and the wound-healing ability of HAECs decreased in asthma samples. Also, the cell proliferation of HAECs was suppressed in the asthmatic injury model and the injury-induced increase of CCND1 protein expressions was inhibited in asthma. Although mRNA and protein expressions of BDNF remained unchanging in healthy HAECs, there was an increase in impaired asthmatic HAECs. Upregulating BDNF led to a decrease in wound-healing ability of HAECs in both healthy children and children with asthma. Simultaneously, overexpressed BDNF reduced the CCND1 protein expressions in healthy HAECs, but had little impact on asthmatic HAECs.ConclusionsBrain-derived neurotrophic factor (BDNF) inhibited wound-healing and cell proliferative ability of human airway epithelial cells (HAECs) in asthmatic children.

Mesenchymal stromal cells protect against vascular damage and depression-like behavior in mice surviving cerebral malaria

BackgroundMalaria is one of the most critical global infectious diseases. Severe systemic inflammatory diseases, such as cerebral malaria, lead to the development of cognitive and behavioral alterations, such as learning disabilities and loss of memory capacity, as well as increased anxiety and depression. The consequences are profound and usually contribute to reduce the patient’s quality of life. There are no therapies to treat the neurological sequelae of cerebral malaria. Mesenchymal stromal cells (MSCs) may be an alternative, since they have been used as therapy for neurodegenerative diseases and traumatic lesions of the central nervous system. So far, no study has investigated the effects of MSC therapy on the blood-brain barrier, leukocyte rolling and adherence in the brain, and depression like-behavior in experimental cerebral malaria.MethodsMale C57BL/6 mice were infected with Plasmodium berghei ANKA (PbA, 1 × 106 PbA-parasitized red blood cells, intraperitoneally). At day 6, PbA-infected animals received chloroquine (25 mg/kg orally for seven consecutive days) as the antimalarial treatment and were then randomized to receive MSCs (1 × 105 cells in 0.05 ml of saline/mouse) or saline (0.05 ml) intravenously. Parasitemia, clinical score, and survival rate were analyzed throughout the experiments. Evans blue assay was performed at 6, 7, and 15 days post-infection (dpi). Behavioral tests were performed at 5 and 15 dpi. Intravital microscopy experiments and brain-derived neurotrophic factor (BDNF) protein expression analyses were performed at 7 dpi, whereas inflammatory mediators were measured at 15 dpi. In vitro, endothelial cells were used to evaluate the effects of conditioned media derived from MSCs (CMMSC) on cell viability by lactate dehydrogenase (LDH) release.ResultsPbA-infected mice presented increased parasitemia, adherent leukocytes, blood-brain barrier permeability, and reduced BDNF protein levels, as well as depression-like behavior. MSCs mitigated behavioral alterations, restored BDNF and transforming growth factor (TGF)-β protein levels, and reduced blood-brain barrier dysfunction and leukocyte adhesion in the brain microvasculature. In a cultured endothelial cell line stimulated with heme, CMMSC reduced LDH release, suggesting a paracrine mechanism of action.ConclusionA single dose of MSCs as adjuvant therapy protected against vascular damage and improved depression-like behavior in mice that survived experimental cerebral malaria.

Imipramine Influences Body Distribution of Supplemental Zinc Which May Enhance Antidepressant Action.

Zinc (Zn) was found to enhance the antidepressant efficacy of imipramine (IMI) in human depression and animal tests/models of depression. However, the underlying mechanism for this effect remains unknown. We measured the effect of intragastric (p.o.) combined administration of IMI (60 mg/kg) and Zn (40 mg Zn/kg) in the forced swim test (FST) in mice. The effect of Zn + IMI on serum, brain, and intestinal Zn concentrations; Zn transporter (ZnT, ZIP) protein levels in the intestine and ZnT in the brain; including BDNF (brain-derived neurotrophic factor) and CREB (cAMP response element-binding protein) protein levels in the brain were evaluated. Finally, the effect of IMI on Zn permeability was measured in vitro in colon epithelial Caco-2 cells. The co-administration of IMI and Zn induced antidepressant-like activity in the FST in mice compared to controls and Zn or IMI given alone. This effect correlated with increased BDNF and the ratio of pCREB/CREB protein levels in the prefrontal cortex (PFC) compared to the control group. Zn + IMI co-treatment increased Zn concentrations in the serum and brain compared to the control group. However, in serum, co-administration of IMI and Zn decreased Zn concentration compared to Zn alone treatment. Also, there was a reduction in the Zn-induced enhancement of ZnT1 protein level in the small intestine. Zn + IMI also induced an increase in the ZnT4 protein level in the PFC compared to the control group and normalized the Zn-induced decrease in the ZnT1 protein level in the hippocampus (Hp). The in vitro studies revealed enhanced Zn permeability (observed as the increased transfer of Zn through the intestinal cell membrane) after IMI treatment. Our data indicate that IMI enhances Zn transfer through the intestinal tract and influences the redistribution of Zn between the blood and brain. These mechanisms might explain the enhanced antidepressant efficacy of combined IMI/Zn treatment observed in the FST in mice.