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Interaction of aerobic exercise and crocin improves memory, learning and hypocampic tau and neurotrophins gene expression in rats treated with trimethytin as a model of Alzheimer's disease

Moghadasi M, Akbari F, Najafi P

Mol Biol Rep, 2024 Jan 16;51(1):111.
PMID: 38227208 DOI: 10.1007/s11033-023-09197-4

INTRODUCTION: Alzheimer's disease (AD) is characterized by progressive cognitive decline and a reduction in hippocampal neurotrophins, in which trimethytin (TMT) infusion causes tangles and neuronal dysfunction, creating an AD-like model in rats. Previous studies have demonstrated that crocin, which has anti-inflammatory properties, can enhance learning, memory acquisition, and cognitive behavior. This study aimed to assess the combined impact of aerobic exercise and crocin on memory, learning, and hippocampal Tau and neurotrophins gene expression in AD-like model rats.
METHODS: Forty male Sprague Dawley rats were randomly divided into five groups: (1) healthy control, (2) Alzheimer's control, (3) endurance training, (4) crocin consumption, and (5) endurance training + crocin. Alzheimer's induction was achieved in groups 2-5 through intraperitoneal injection of 8 mg/kg TMT. Rats in groups 3 and 5 engaged in treadmill running three sessions per week, 15-30 min per session, at a speed of 15-20 m/min for eight weeks, and groups 4 and 5 received daily crocin supplementation of 25 mg/kg.
RESULTS: Alzheimer's induction with TMT showed significant reduction in memory, learning, NGF, BDNF, and TrkB gene expression, and increase in tau gene expression (all p

Matched MeSH terms: Brain-Derived Neurotrophic Factor/genetics
New insights on brain-derived neurotrophic factor epigenetics: from depression to memory extinction

Poon CH, Heng BC, Lim LW

Ann N Y Acad Sci, 2021 01;1484(1):9-31.
PMID: 32808327 DOI: 10.1111/nyas.14458

Advances in characterizing molecular profiles provide valuable insights and opportunities for deciphering the neuropathology of depression. Although abnormal brain-derived neurotrophic factor (BDNF) expression in depression has gained much support from preclinical and clinical research, how it mediates behavioral alterations in the depressed state remains largely obscure. Environmental factors contribute significantly to the onset of depression and produce robust epigenetic changes. Epigenetic regulation of BDNF, as one of the most characterized gene loci in epigenetics, has recently emerged as a target in research on memory and psychiatric disorders. Specifically, epigenetic alterations of BDNF exons are heavily involved in mediating memory functions and antidepressant effects. In this review, we discuss key research on stress-induced depression from both preclinical and clinical studies, which revealed that differential epigenetic regulation of specific BDNF exons is associated with depression pathophysiology. Considering that BDNF has a central role in depression, we argue that memory extinction, an adaptive response to fear exposure, is dependent on BDNF modulation and holds promise as a prospective target for alleviating or treating depression and anxiety disorders.

Matched MeSH terms: Brain-Derived Neurotrophic Factor/genetics*
Fulltext Missense Mutation of Brain Derived Neurotrophic Factor (BDNF) Alters Neurocognitive Performance in Patients with Mild Traumatic Brain Injury: A Longitudinal Study

Narayanan V, Veeramuthu V, Ahmad-Annuar A, Ramli N, Waran V, Chinna K, et al.

PLoS One, 2016;11(7):e0158838.
PMID: 27438599 DOI: 10.1371/journal.pone.0158838

The predictability of neurocognitive outcomes in patients with traumatic brain injury is not straightforward. The extent and nature of recovery in patients with mild traumatic brain injury (mTBI) are usually heterogeneous and not substantially explained by the commonly known demographic and injury-related prognostic factors despite having sustained similar injuries or injury severity. Hence, this study evaluated the effects and association of the Brain Derived Neurotrophic Factor (BDNF) missense mutations in relation to neurocognitive performance among patients with mTBI. 48 patients with mTBI were prospectively recruited and MRI scans of the brain were performed within an average 10.1 (SD 4.2) hours post trauma with assessment of their neuropsychological performance post full Glasgow Coma Scale (GCS) recovery. Neurocognitive assessments were repeated again at 6 months follow-up. The paired t-test, Cohen's d effect size and repeated measure ANOVA were performed to delineate statistically significant differences between the groups [wildtype G allele (Val homozygotes) vs. minor A allele (Met carriers)] and their neuropsychological performance across the time point (T1 = baseline/ admission vs. T2 = 6th month follow-up). Minor A allele carriers in this study generally performed more poorly on neuropsychological testing in comparison wildtype G allele group at both time points. Significant mean differences were observed among the wildtype group in the domains of memory (M = -11.44, SD = 10.0, p = .01, d = 1.22), executive function (M = -11.56, SD = 11.7, p = .02, d = 1.05) and overall performance (M = -6.89 SD = 5.3, p = .00, d = 1.39), while the minor A allele carriers showed significant mean differences in the domains of attention (M = -11.0, SD = 13.1, p = .00, d = .86) and overall cognitive performance (M = -5.25, SD = 8.1, p = .01, d = .66).The minor A allele carriers in comparison to the wildtype G allele group, showed considerably lower scores at admission and remained impaired in most domains across the timepoints, although delayed signs of recovery were noted to be significant in the domains attention and overall cognition. In conclusion, the current study has demonstrated the role of the BDNF rs6265 Val66Met polymorphism in influencing specific neurocognitive outcomes in patients with mTBI. Findings were more detrimentally profound among Met allele carriers.

Matched MeSH terms: Brain-Derived Neurotrophic Factor/genetics*
BDNF rs6265 polymorphism and drug addiction: a systematic review and meta-analysis

Haerian BS

Pharmacogenomics, 2013 Dec;14(16):2055-65.
PMID: 24279859 DOI: 10.2217/pgs.13.217

A majority of studies have shown a link between the common functional rs6265 polymorphism of the BDNF gene and susceptibility to drug dependence. However, the pattern of results is inconsistent. To precisely evaluate this association, a systematic review and meta-analysis of previous case-control reports was conducted. Data from 20 studies containing 9419 participants (4665 cases and 4754 controls) conducted between 2004 and 2013 restricted to alcohol, nicotine, heroin, substance and methamphetamine dependency were meta-analyzed. Following quality control of the results, a significant association between C allele and methamphetamine dependence remained in south Asian subjects (p = 0.004). Similar results were detected in south Asian subjects for methamphetamine dependence and in Chinese subjects for heroin dependence under an autosomal codominant genotype model (TT vs CC, p = 0.005 and p = 0.0004, respectively). In conclusion, the rs6265 polymorphism may be a risk factor for methamphetamine dependence in south Asian subjects or for heroin dependence in Chinese subjects.

Matched MeSH terms: Brain-Derived Neurotrophic Factor/genetics*
Fulltext BDNF and DARPP-32 genes are not risk factors for schizophrenia in the Malay population

Loh HC, Tang PY, Tee SF, Chow TJ, Cheah YC, Singh SS

Genet. Mol. Res., 2012;11(1):725-30.
PMID: 22576830 DOI: 10.4238/2012.March.22.2

A number of studies have pointed to the association of BDNF (brain-derived neurotrophic factor) and DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, 32 kDa) with schizophrenia. The purpose of this study was to determine whether these two genes are involved in the pathogenesis of schizophrenia in the Malay population. Two single nucleotide polymorphisms Val66Met of BDNF, -2036C>G and g.1238delG of DARPP-32 were genotyped in the Malay population in 200 patients with schizophrenia and 256 healthy controls. Analysis of allele and genotype frequencies in these two groups revealed no significant association of BDNF or DARPP-32 polymorphisms with schizophrenia in Malays. This is the first such association study in the Malay population.

Matched MeSH terms: Brain-Derived Neurotrophic Factor/genetics*
Association of BDNF Polymorphisms with the Risk of Epilepsy: a Multicenter Study

Sha'ari HM, Haerian BS, Baum L, Tan HJ, Rafia MH, Kwan P, et al.

Mol Neurobiol, 2016 07;53(5):2869-2877.
PMID: 25876511 DOI: 10.1007/s12035-015-9150-1

Epilepsy is a common neurological disease characterized by recurrent unprovoked seizures. Evidence suggested that abnormal activity of brain-derived neurotrophic factor (BDNF) contributes to the pathogenesis of epilepsy. Some previous studies identified association between genetic variants of BDNF and risk of epilepsy. In this study, this association has been examined in the Hong Kong and Malaysian epilepsy cohorts. Genomic DNA of 6047 subjects (1640 patients with epilepsy and 4407 healthy individuals) was genotyped for rs6265, rs11030104, rs7103411, and rs7127507 polymorphisms by using Sequenom MassArray and Illumina HumanHap 610-Quad or 550-Duo BeadChip arrays techniques. Results showed significant association between rs6265 T, rs7103411 C, and rs7127507 T and cryptgenic epilepsy risk (p = 0.00003, p = 0.0002, and p = 0.002, respectively) or between rs6265 and rs7103411 and symptomatic epilepsy risk in Malaysian Indians (TT vs. CC, p = 0.004 and T vs. C, p = 0.0002, respectively) as well as between rs6265 T and risk of cryptogenic epilepsy in Malaysian Chinese (p = 0.005). The Trs6265-Crs7103411-Trs7127507 was significantly associated with cryptogenic epilepsy in Malaysian Indians (p = 0.00005). In conclusion, our results suggest that BDNF polymorphisms might contribute to the risk of epilepsy in Malaysian Indians and Chinese.

Matched MeSH terms: Brain-Derived Neurotrophic Factor/genetics*
Fulltext Screening of brain-derived neurotrophic factor (BDNF) single nucleotide polymorphisms and plasma BDNF levels among Malaysian major depressive disorder patients

Aldoghachi AF, Tor YS, Redzun SZ, Lokman KAB, Razaq NAA, Shahbudin AF, et al.

PLoS One, 2019;14(1):e0211241.
PMID: 30677092 DOI: 10.1371/journal.pone.0211241

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a neurotrophin found in abundance in brain regions such as the hippocampus, cortex, cerebellum and basal forebrain. It has been associated with the risk of susceptibility to major depressive disorder (MDD). This study aimed to determine the association of three BDNF variants (rs6265, rs1048218 and rs1048220) with Malaysian MDD patients.
METHODS: The correlation of these variants to the plasma BDNF level among Malaysian MDD patients was assessed. A total of 300 cases and 300 matched controls recruited from four public hospitals within the Klang Valley of Selangor State, Malaysia and matched for age, sex and ethnicity were screened for BDNF rs6265, rs1048218 and rs1048220 using high resolution melting (HRM).
FINDINGS: BDNF rs1048218 and BDNF rs1048220 were monomorphic and were excluded from further analysis. The distribution of the alleles and genotypes for BDNF rs6265 was in Hardy-Weinberg equilibrium for the controls (p = 0.13) but was in Hardy Weinberg disequilibrium for the cases (p = 0.011). Findings from this study indicated that having BDNF rs6265 in the Malaysian population increase the odds of developing MDD by 2.05 folds (95% CI = 1.48-3.65). Plasma from 206 cases and 206 controls were randomly selected to measure the BDNF level using enzyme-linked immunosorbent assay (ELISA). A significant decrease in the plasma BDNF level of the cases as compared to controls (p<0.0001) was observed. However, there was no evidence of the effect of the rs6265 genotypes on the BDNF level indicating a possible role of other factors in modulating the BDNF level that warrants further investigation.
CONCLUSION: The study indicated that having the BDNF rs6265 allele (A) increase the risk of developing MDD in the Malaysian population suggesting a possible role of BDNF in the etiology of the disorder.

Matched MeSH terms: Brain-Derived Neurotrophic Factor/genetics*
Association of brain-derived neurotrophic factor (Val66Met) genetic polymorphism with methamphetamine dependence in a Malaysian population

Sim MS, Mohamed Z, Hatim A, Rajagopal VL, Habil MH

Brain Res, 2010 Oct 21;1357:91-6.
PMID: 20736000 DOI: 10.1016/j.brainres.2010.08.053

Methamphetamine is a highly addictive psychostimulant that has surged in popularity worldwide in the last decade. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, is widely expressed in the adult mammalian brain and plays an important role in the long-term survival, differentiation, and outgrowth of neurons. Previous studies suggested that the BDNF gene may be involved in the mechanisms underlying substance dependence. This study investigated the association of the BDNF gene Val66Met polymorphism with methamphetamine dependence and with psychosis in a Malaysian population with different ethnicities. The BDNF Val66Met polymorphism was genotyped by PCR-RFLP in 186 male methamphetamine-dependent subjects and in 154 male controls of four different ethnicities, namely, Malay, Chinese, Kadazan-Dusun, and Bajau. Our results showed that the distribution of the BDNF Val66Met genotype in Chinese subjects with methamphetamine dependence (OR=2.6, p=0.015) and methamphetamine psychosis (OR=0.2, p = 0.034) were significant compared with controls. The frequency of the 66Val allele in methamphetamine-dependent subjects was higher than that in the control group, suggesting that the 66Val carriers are more susceptible to methamphetamine dependence. However, 66Val allele frequency in other ethnicities was not significantly different from the controls. The results of the study also showed that in the Chinese methamphetamine-dependent subjects, there was a difference in allele frequency when comparing those who developed psychosis and those who did not. Our findings suggest that the BDNF Val66Met polymorphism may contribute to methamphetamine dependence and psychosis in the Chinese population but not in other Malaysian ethnicities.

Matched MeSH terms: Brain-Derived Neurotrophic Factor/genetics*
Association of brain-derived neurotrophic factor valine to methionine polymorphism with sexual dysfunction following selective serotonin reuptake inhibitor treatment in female patients with major depressive disorder

Nazree NE, Mohamed Z, Reynolds GP, Mohd Zain S, Masiran R, Sidi H, et al.

Asia Pac Psychiatry, 2016 Dec;8(4):260-268.
PMID: 27787964 DOI: 10.1111/appy.12210

INTRODUCTION: The occurrence of female sexual dysfunction (FSD) in patients with major depressive disorder (MDD) receiving selective serotonin reuptake inhibitors (SSRIs) treatment gives negative impacts on patients' quality of life and causes treatment discontinuation. We aimed to investigate whether genetic polymorphism of identified candidate gene is associated with FSD in our study population.
METHODS: This is a cross-sectional study. A total of 95 female patients with MDD who met the criteria of the study were recruited and were specifically assessed on the sexual function by trained psychiatrists. Patients' DNA was genotyped for BDNF Val66Met polymorphism using real-time polymerase chain reaction.
RESULTS: The prevalence of FSD in this study is 31.6%. In the FSD group, patients with problematic marriage were significantly more frequent compared with patients who did not have problematic marriage (P = 0.009). Significant association was detected in the lubrication domain with BDNF Val66Met polymorphism (P = 0.030) using additive genetic model, with even stronger association when using the recessive model (P = 0.013).
DISCUSSION: This study suggested that there was no significant association between BDNF Val66Met with FSD. However, this polymorphism is significantly associated with lubrication disorder in patients treated with SSRIs.

Matched MeSH terms: Brain-Derived Neurotrophic Factor/genetics*
Ifenprodil Reduced Expression of Activated Microglia, BDNF and DREAM Proteins in the Spinal Cord Following Formalin Injection During the Early Stage of Painful Diabetic Neuropathy in Rats

Ismail CAN, Suppian R, Ab Aziz CB, Long I

J Mol Neurosci, 2021 Feb;71(2):379-393.
PMID: 32671697 DOI: 10.1007/s12031-020-01661-1

The pharmacological inhibition of glial activation is one of the new approaches for combating neuropathic pain in which the role of glia in the modulation of neuropathic pain has attracted significant interest and attention. Neuron-glial crosstalk is achieved with N-methyl-D-aspartate-2B receptor (NMDAR-2B) activation. This study aims to determine the effect of ifenprodil, a potent noncompetitive NMDAR-2B antagonist, on activated microglia, brain-derived neurotrophic factors (BDNF) and downstream regulatory element antagonist modulator (DREAM) protein expression in the spinal cord of streptozotocin-induced painful diabetic neuropathy (PDN) rats following formalin injection. In this experimentation, 48 Sprague-Dawley male rats were randomly selected and divided into four groups: (n = 12): control, PDN, and ifenprodil-treated PDN rats at 0.5 μg or 1.0 μg for 7 days. Type I diabetes mellitus was then induced by injecting streptozotocin (60 mg/kg, i.p.) into the rats which were then over a 2-week period allowed to progress into the early phase of PDN. Ifenprodil was administered in PDN rats while saline was administered intrathecally in the control group. A formalin test was conducted during the fourth week to induce inflammatory nerve injury, in which the rats were sacrificed at 72 h post-formalin injection. The lumbar enlargement region (L4-L5) of the spinal cord was dissected for immunohistochemistry and western blot analyses. The results demonstrated a significant increase in formalin-induced flinching and licking behavior with an increased spinal expression of activated microglia, BDNF and DREAM proteins. It was also shown that the ifenprodil-treated rats following both doses reduced the extent of their flinching and duration of licking in PDN in a dose-dependent manner. As such, ifenprodil successfully demonstrated inhibition against microglia activation and suppressed the expression of BDNF and DREAM proteins in the spinal cord of PDN rats. In conclusion, ifenprodil may alleviate PDN by suppressing spinal microglia activation, BDNF and DREAM proteins.

Matched MeSH terms: Brain-Derived Neurotrophic Factor/genetics
Tumour biology of obesity-related cancers: understanding the molecular concept for better diagnosis and treatment

Teoh SL, Das S

Tumour Biol., 2016 Nov;37(11):14363-14380.
PMID: 27623943

Obesity continues to be a major global problem. Various cancers are related to obesity and proper understanding of their aetiology, especially their molecular tumour biology is important for early diagnosis and better treatment. Genes play an important role in the development of obesity. Few genes such as leptin, leptin receptor encoded by the db (diabetes), pro-opiomelanocortin, AgRP and NPY and melanocortin-4 receptors and insulin-induced gene 2 were linked to obesity. MicroRNAs control gene expression via mRNA degradation and protein translation inhibition and influence cell differentiation, cell growth and cell death. Overexpression of miR-143 inhibits tumour growth by suppressing B cell lymphoma 2, extracellular signal-regulated kinase-5 activities and KRAS oncogene. Cancers of the breast, uterus, renal, thyroid and liver are also related to obesity. Any disturbance in the production of sex hormones and insulin, leads to distortion in the balance between cell proliferation, differentiation and apoptosis. The possible mechanism linking obesity to cancer involves alteration in the level of adipokines and sex hormones. These mediators act as biomarkers for cancer progression and act as targets for cancer therapy and prevention. Interestingly, many anti-cancerous drugs are also beneficial in treating obesity and vice versa. We also reviewed the possible link in the mechanism of few drugs which act both on cancer and obesity. The present review may be important for molecular biologists, oncologists and clinicians treating cancers and also pave the way for better therapeutic options.

Matched MeSH terms: Brain-Derived Neurotrophic Factor/genetics
Gene Therapy Approaches in an Autoimmune Demyelinating Disease: Multiple Sclerosis

Islam MA, Kundu S, Hassan R

Curr Gene Ther, 2020;19(6):376-385.
PMID: 32141417 DOI: 10.2174/1566523220666200306092556

Multiple Sclerosis (MS) is the most common autoimmune demyelinating disease of the Central Nervous System (CNS). It is a multifactorial disease which develops in an immune-mediated way under the influences of both genetic and environmental factors. Demyelination is observed in the brain and spinal cord leading to neuro-axonal damage in patients with MS. Due to the infiltration of different immune cells such as T-cells, B-cells, monocytes and macrophages, focal lesions are observed in MS. Currently available medications treating MS are mainly based on two strategies; i) to ease specific symptoms or ii) to reduce disease progression. However, these medications tend to induce different adverse effects with limited therapeutic efficacy due to the protective function of the blood-brain barrier. Therefore, researchers have been working for the last four decades to discover better solutions by introducing gene therapy approaches in treating MS generally by following three strategies, i) prevention of specific symptoms, ii) halt or reverse disease progression and iii) heal CNS damage by promoting remyelination and axonal repair. In last two decades, there have been some remarkable successes of gene therapy approaches on the experimental mice model of MS - experimental autoimmune encephalomyelitis (EAE) which suggests that it is not far that the gene therapy approaches would start in human subjects ensuring the highest levels of safety and efficacy. In this review, we summarised the gene therapy approaches attempted in different animal models towards treating MS.

Matched MeSH terms: Brain-Derived Neurotrophic Factor/genetics
Fulltext Embelin Improves the Spatial Memory and Hippocampal Long-Term Potentiation in a Rat Model of Chronic Cerebral Hypoperfusion

Bhuvanendran S, Bakar SNS, Kumari Y, Othman I, Shaikh MF, Hassan Z

Sci Rep, 2019 10 10;9(1):14507.
PMID: 31601902 DOI: 10.1038/s41598-019-50954-y

Alzheimer's disease (AD) is the second most occurring neurological disorder after stroke and is associated with cerebral hypoperfusion, possibly contributing to cognitive impairment. In the present study, neuroprotective and anti-AD effects of embelin were evaluated in chronic cerebral hypoperfusion (CCH) rat model using permanent bilateral common carotid artery occlusion (BCCAO) method. Rats were administered with embelin at doses of 0.3, 0.6 or 1.2 mg/kg (i.p) on day 14 post-surgery and tested in Morris water maze (MWM) followed by electrophysiological recordings to access cognitive abilities and synaptic plasticity. The hippocampal brain regions were extracted for gene expression and neurotransmitters analysis. Treatment with embelin at the doses of 0.3 and 0.6 mg/kg significantly reversed the spatial memory impairment induced by CCH in rats. Embelin treatment has significantly protected synaptic plasticity impairment as assessed by hippocampal long-term potentiation (LTP) test. The mechanism of this study demonstrated that embelin treatment alleviated the decreased expression of BDNF, CREB1, APP, Mapt, SOD1 and NFκB mRNA levels caused by CCH rats. Furthermore, treatment with embelin demonstrated neuromodulatory activity by its ability to restore hippocampal neurotransmitters. Overall these data suggest that embelin improve memory and synaptic plasticity impairment in CCH rats and can be a potential drug candidate for neurodegenerative disease-related cognitive disorders.

Matched MeSH terms: Brain-Derived Neurotrophic Factor/genetics

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