The seizure-related phenotype of brain-derived neurotrophic factor knockdown mice

The present investigation focused on the seizure-related phenotype of mice lacking one allele of brain-derived neurotrophic factor. Thresholds for producing seizures in brain-derived neurotrophic factor wild-type and brain-derived neurotrophic factor heterozygous mice were compared in several seizure models, including thresholds for electrically-induced clonic, tonic-clonic and 6 Hz limbic seizures, as well as seizures induced chemically by kainate, pilocarpine and pentylenetetrazol. In addition, the rate of amygdala kindling, as well as pre- and post-kindling seizure thresholds was determined. Seizure thresholds for clonic and tonic-clonic electrically induced seizures did not differ between brain-derived neurotrophic factor wild-type and heterozygous mice. However, heterozygous mice had higher thresholds for 6 Hz limbic seizures compared with wild-type mice. Heterozygous mice also required larger doses of kainate to produce limbic seizures. Somewhat surprisingly, heterozygous mice required significantly lower doses of pilocarpine to produce limbic seizures. However, heterozygous mice required a higher dose of pentylenetetrazol to induce twitches, but not clonic seizures, compared with wild-type mice. In addition, heterozygous mice required more current to elicit focal afterdischarges in the amygdala both pre- and post-kindling than did wild-type mice, and, heterozygous mice kindled more slowly than wild-type mice. The present findings provide additional support for the hypothesis that brain-derived neurotrophic factor is involved not only in normal excitability, but may also be involved in abnormal excitability such as occurs in seizure disorders and epileptogenesis.     

Involvement of brain-derived neurotrophic factor (BDNF) in MP4-induced autoimmune encephalomyelitis

The role of brain-derived neurotrophic factor (BDNF) in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) is still unclear. Here we investigate the clinical course, CNS histopathology and peripheral antigen-specific immunity in MP4-induced EAE of BDNF (−/+) mice. We demonstrate that these mice displayed less severe disease compared to BDNF (+/+) mice, reflected by decreased inflammation and demyelination. In correspondence to diminished frequencies of T and B cells in CNS infiltrates, the peripheral MP4-specific T_H1/T_H17 response was attenuated in BDNF (−/+), but not in wild-type animals. In contrast, immunization with ovalbumin triggered similar frequencies of IFN-γ- and IL-17-secreting T cells in both groups. The cytokine secretion and proliferative activity upon mitogen stimulation did not reveal any global defect of T cell function in BDNF (−/+) mice. By influencing the antigen-specific immune response in autoimmune encephalomyelitis, BDNF may support and maintain the disease in ways that go beyond its alleged neuroprotective role.     

Chronic ethanol ingestion, type 2 diabetes mellitus, and brain-derived neurotrophic factor (BDNF) in rats

Chronic alcohol consumption contributes to the development of type 2 diabetes mellitus (T2DM) while decreasing the level of brain-derived neurotrophic factor (BDNF). BDNF may be an important regulator of glucose metabolism, so it may be associated with an increased risk for T2DM in alcoholism. We evaluated the association of chronic heavy alcohol exposure, T2DM and BDNF level. Ten week-old type 2 diabetic OLETF rats and non-diabetic LETO rats of similar weight were used. The rats were randomized by weight into four treatment groups: (1) OLETF-Ethanol (O-E, n=13), (2) OLETF-Control (O-C, n=15), (3) LETO-Ethanol (L-E, n=11), and (4) LETO-Control (L-C, n=14). The ethanol groups were fed an isocaloric liquid diet containing ethanol while the control groups were fed with the same diet containing maltose-dextran over a 6-week period using a pair-feeding control model in order to regulate different caloric ingestion. After 6 weeks of feeding, an Intraperitoneal Glucose Tolerance Test (IP-GTT) was performed and BDNF levels were analyzed. Prior to IP-GTT, the mean glucose levels in the O-E, O-C, L-E, and L-C groups were 90.38±12.84, 102.13±5.04, 95.18±6.43, and 102.36±4.43mg/dL, respectively. Thirty minutes after intraperitoneal injection, the mean glucose levels were 262.62±63.77, 229.07±51.30, 163.45±26.63, and 156.64±34.42mg/dL, respectively; the increased amount of the mean glucose level in the O-E group was significantly higher than that in the O-C group (p<0.05). One hundred twenty minutes after intraperitoneal injection, the mean glucose levels were 167.38±45.37, 121.20±18.54, 106.73±6.94, and 104.57±9.49mg/dL, respectively; the increased amount of the mean glucose level in the O-E group was significantly higher than that in the O-C group (p<0.01). The difference in mean glucose levels between the O-E group and O-C group was still significant even after adjusting for time (p<0.05). Mean BDNF levels were 405.95±326.16, 618.23±462.15, 749.18±599.93, and 1172.00±839.17pg/mL, respectively; mean BDNF level in the O-E group was significantly lower than the L-C group (p<0.05). In conclusion, the results of the present study suggest that chronic heavy alcohol ingestion may aggravate T2DM and may possibly lower BDNF level.     

Involvement of brain-derived neurotrophic factor (BDNF) in the development of periodontal Ruffini endings

The periodontal Ruffini ending has been reported to show immunoreactivity for tyrosine kinase B (trkB), the high-affinity receptor for brain-derived neurotrophic factor (BDNF), in the periodontal ligament of the rat incisor. Furthermore, adult heterozygous BDNF-mutant mice showed malformation and reduction of the periodontal Ruffini endings. To investigate further roles of BDNF in these structures, the development, distribution, and terminal morphology of Ruffini endings were examined in the incisor periodontal ligament of heterozygous and homozygous BDNF mutant mice, as well as in the wild-type littermate by immunohistochemistry for protein gene product (PGP) 9.5, a general neuronal marker. A similar distribution and terminal formation of PGP 9.5-immunoreactive nerve fibers was recognized in the periodontal ligament of all phenotypes at postnatal week (PW) 1. At this stage, the nerve fibers had a beaded appearance, but did not form the periodontal Ruffini endings. At PW2, the heterozygous and wild-type mice started to show ramified nerve fibers resembling the mature shape of periodontal Ruffini endings. At PW3, the Ruffini endings occurred in the periodontal ligament of the wild-type and heterozygous mice. While the Ruffini endings of the wild-type mice appeared either ruffled or smooth, as reported previously, most of these structures showed a smooth outline in the heterozygous mice. The homozygous mice lacked the typical Ruffini endings at PW3. In the quantitative analysis, homozygous mice had the smallest percentages of PGP 9.5-immunoreactive areas at the same postnatal periods, but there were no significant differences between wild-type and heterozygous mice during PW1-3. These findings suggest a possible involvement of BDNF during the postnatal development and, in particular, the maturation of periodontal Ruffini endings. Furthermore, other neurotrophins may play a role in the development and/or early maturation of the periodontal nerve fibers, as indicated by the presence of nerve fibers in the BDNF-homozygous mice.     

Low brain-derived neurotrophic factor (BDNF) levels in serum of Huntington's disease patients.

Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms and by a progressive degeneration of neurons in basal ganglia and in brain cortex. Brain-derived neurotrophic factor (BDNF) is a pro-survival factor for striatal neurons. Some evidence implicates a brain BDNF deficiency, related to mutated huntingtin expression, in the selective vulnerability of striatal neurons in HD. We compared BDNF serum levels in 42 patients with HD (range 28-72 years, mean age 51.9 +/- 11.5), and 42 age-matched healthy subjects (range 25-68 years, mean age 48.2 +/- 12.5). We evaluated the potential relationship between BDNF serum levels, CAG repeat number (range 40-54, mean 44.8 +/- 3.4) and duration of illness (range 6-228 months, mean 103.6 +/- 62.1). Serum BDNF levels were significantly lower in patients than in age-matched healthy subjects. Lower BDNF levels were associated with a longer CAG repeat length and a longer duration of illness. Severity of the illness, as assessed by the Unified Huntington's Disease Rating Scale (UHDRS) motor and cognitive scores, was negatively related to serum BDNF levels. These results in vivo confirm that the huntingtin mutation causes BDNF production to decline and show that the BDNF deficiency is detectable in HD patients' sera. Further studies on a larger sample size should confirm whether BDNF concentrations in patients' serum could be a useful clinical marker related to the patients' disease phenotype.     

Relationship of serum brain-derived neurotrophic factor (BDNF) and health-related lifestyle in healthy human subjects

The associations between serum brain-derived neurotrophic factor (BDNF) levels and several health-related lifestyle factors were evaluated in 85 healthy human subjects. Results showed that the frequency of fruit intake, exercise and television watching were associated with serum BDNF level. There was a higher serum BDNF level from the group with fruit intake five to six times per week. Subjects with moderate frequency of exercise (1-30 times of 30 min exercise per month) showed higher serum BDNF level than the group with exercise more than 30 times per month. There was a significant positive correlation between serum BDNF and the daily average watching television time in the younger age group (18-35). The result of this study supports the need for larger studies with different health-related lifestyle in healthy subjects or subjects with disorders.     

Association between the brain-derived neurotrophic factor (BDNF) gene and schizophrenia in the Chinese population

Brain-derived neurotrophic factor (BDNF) belongs to a family of the neurotrophin which plays important roles in the development of the brain. BDNF has been suggested as a factor that increases the risk of schizophrenia. In this study, we genotyped three single nucleotide polymorphisms (SNPs) in the BDNF gene using a set sample of Han Chinese subjects consisting of 560 schizophrenes and 576 controls. No significant differences were found for either the genotype or allele distribution of analyzed polymorphisms, nor was any gender-specific association found. Thus, our data suggest that the BDNF gene may not be an important factor in susceptibility to schizophrenia.     

Continuous brain-derived neurotrophic factor (BDNF) infusion after methylprednisolone treatment in severe spinal cord injury

Although methylprednisolone (MP) is the standard of care in acute spinal cord injury (SCI), its functional outcome varies in clinical situation. Recent report demonstrated that MP depresses the expression of growth-promoting neurotrophic factors after acute SCI. The present study was designed to investigate whether continuous infusion of brain-derived neurotrophic factor (BDNF) after MP treatment promotes functional recovery in severe SCI. Contusion injury was produced at the T10 vertebral level of the spinal cord in adult rats. The rats received MP intravenously immediately after the injury and BDNF was infused intrathecally using an osmotic mini-pump for six weeks. Immunohistochemical methods were used to detect ED-1, Growth associated protein-43 (GAP-43), neurofilament (NF), and choline acethyl transferase (ChAT) levels. BDNF did not alter the effect of MP on hematogenous inflammatory cellular infiltration. MP treatment with BDNF infusion resulted in greater axonal survival and regeneration compared to MP treatment alone, as indicated by increases in NF and GAP-43 gene expression. Adjunctive BDNF infusion resulted in better locomotor test scores using the Basso-Beattie-Bresnahan (BBB) test. This study demonstrated that continuous infusion of BDNF after initial MP treatment improved functional recovery after severe spinal cord injury without dampening the acute effect of MP.     

Acute prefrontal cortex transcranial magnetic stimulation in healthy volunteers: no effects on brain-derived neurotrophic factor (BDNF) concentrations in serum

BACKGROUND: Transcranial magnetic stimulation (TMS) of the dorsolateral prefrontal cortex is a brain stimulation technique widely used to treat depression. BDNF serum concentrations have been shown to be decreased in patients with major depressive disorder and can be upregulated by several antidepressive treatment strategies including repetitive TMS. METHODS: In this study we were interested whether acute TMS evolves effects on serum BDNF concentrations in 42 healthy volunteers. RESULTS: Mean BDNF serum concentration in 19 male and 23 female volunteers was 10.70+/-3.6 ng/ml (n=42) at baseline, and 10.76+/-3.9 ng/ml (n=42) after TMS treatment. BDNF serum levels did not change after acute TMS (n=42, Z=-0.44, p=0.965). BDNF serum concentrations at baseline did not differ between male (n=19, 10.05+/-2.6 ng/ml) and female (n=23, 11.25+/-4.27 ng/ml) participants of the study (n=42, Z=-0.91, p=0.363). CONCLUSIONS: Our result suggests that TMS does not change BDNF serum concentrations immediately in healthy human volunteers.     

Plasma and serum brain-derived neurotrophic factor (BDNF) in depressed patients during 1 year of antidepressant treatments

BACKGROUND: Brain-derived neurotrophic factor (BDNF) has been hypothesized to be involved in the neurobiology of major depression. The aim of this study was to assess the possible relationships between depressive symptoms and serum and/or plasma BDNF levels during 1 year of antidepressant treatment. METHODS: Plasma and serum BDNF levels were assayed in 15 drug-free depressed patients and in 15 healthy control subjects at baseline and the 1st, 3rd, 6th and 12th month of antidepressant treatment. RESULTS: At baseline, patients' serum and plasma BDNF levels were significantly lower (p<.001 and p=.004, respectively) than those found in healthy control subjects. However, while from the 1st month of treatment patients' plasma BDNF levels did not differ significantly from those observed in healthy control subjects, serum BDNF levels in patients remained significantly lower at all times. LIMITATIONS: The main limitations of the current study are represented by the small sample size and the high discontinuation rate. CONCLUSIONS: Untreated depressed patients showed reduced baseline serum and plasma BDNF levels, as compared with control subjects. The clinical improvement paralleled the normalization of plasma BDNF after 1 month of treatment, while, at every assessment time, patients' serum BDNF levels were lower than those of control subjects. This would suggest that serum BDNF might represent a non-specific trait marker of depression.     

Platelet-derived growth factor (PDGF-BB) and brain-derived neurotrophic factor (BDNF) induce striatal neurogenesis in adult rats with 6-hydroxydopamine lesions

The effects of i.c.v. infused platelet-derived growth factor and brain-derived neurotrophic factor on cell genesis, as assessed with bromodeoxyuridine (BrdU) incorporation, were studied in adult rats with unilateral 6-hydroxydopamine lesions. Both growth factors increased the numbers of newly formed cells in the striatum and substantia nigra to an equal extent following 10 days of treatment. At 3 weeks after termination of growth factor treatment, immunostaining of BrdU-labeled cells with the neuronal marker NeuN revealed a significant increase in newly generated neurons in the striatum. In correspondence, many doublecortin-labeled neuroblasts were also observed in the denervated striatum following growth factor treatment. Further evaluation suggested that a subset of these new neurons expresses the early marker for striatal neurons Pbx. However, no BrdU-positive cells were co-labeled with DARPP-32, a protein expressed by mature striatal projection neurons. Both in the striatum and in the substantia nigra there were no indications of any newly born cells differentiating into dopaminergic neurons following growth factor treatment, such that BrdU-labeled cells never co-expressed tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis. In conclusion, our results suggest that administration of these growth factors is capable of recruiting new neurons into the striatum of hemiparkinsonian rats.     

Serum brain-derived neurotrophic factor (BDNF) concentrations in pregnant women with post-traumatic stress disorder and comorbid depression

There is accumulating evidence for the role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of depression. However, the role of BDNF in the pathophysiology of post-traumatic stress disorder (PTSD) remains controversial, and no study has assessed BDNF concentrations among pregnant women with PTSD. We examined early-pregnancy BDNF concentrations among women with PTSD with and without depression. A total of 2928 women attending prenatal care clinics in Lima, Peru, were recruited. Antepartum PTSD and depression were evaluated using PTSD Checklist—Civilian Version (PCL-C) and Patient Health Questionnaire-9 (PHQ-9) scales, respectively. BDNF concentrations were measured in a subset of the cohort (N?=?944) using a competitive enzyme-linked immunosorbent assay (ELISA). Logistic regression procedures were used to estimate odds ratios (OR) and 95 % confidence intervals (95 % CI). Antepartum PTSD (37.4 %) and depression (27.6 %) were prevalent in this cohort of low-income pregnant Peruvian women. Approximately 19.9 % of participants had comorbid PTSD-depression. Median serum BDNF concentrations were lower among women with comorbid PTSD-depression as compared with women without either condition (median [interquartile range], 20.44 [16.97–24.30] vs. 21.35 [17.33–26.01]?ng/ml; P?=?0.06). Compared to the referent group (those without PTSD and depression), women with comorbid PTSD-depression were 1.52-fold more likely to have low (<25.38 ng/ml) BDNF concentrations (OR?=?1.52; 95 % CI 1.00–2.31). We observed no evidence of reduced BDNF concentrations among women with isolated PTSD. BDNF concentrations in early pregnancy were only minimally and non-significantly reduced among women with antepartum PTSD. Reductions in BDNF concentrations were more pronounced among women with comorbid PTSD-depression.     

A preliminary association study between brain-derived neurotrophic factor (BDNF) haplotype and late-onset depression in mainland Chinese

ObjectiveThe present study aimed to assess the association of genotypes and haplotypes in brain-derived neurotrophic factor (BDNF) polymorphisms with late-onset depression (LOD) in a Chinese Han population.Method144 subjects with LOD and 110 control subjects were recruited for the study, assessed using the Hamilton Rating Scale for Depression, and genotyped for 712G/A, 270C/T, 196A/G and 11757G/C variants by polymerase chain reaction.ResultsNo differences were found in the frequencies of the alleles and genotypes of tested BDNF gene between LOD patients and normal group. Interestingly, the distributions of 712G–270T, 196A–11757G, 196G–11757C, 712G–196A–11757G, 712G–196G–11757C, 270C–196A–11757G, 270C–196G–11757C, 712G–270C–196A–11757G, 712G–270C–196G–11757C haplotypes were significantly higher in LOD compared to healthy controls (all P < 0.05).ConclusionThe results tentatively suggest that BDNF haplotypes might be the susceptibility for LOD.     

Peripheral lipopolysaccharide administration transiently affects expression of brain-derived neurotrophic factor, corticotropin and proopiomelanocortin in mouse brain

Peripheral inflammation induced by intraperitoneal (i.p.) injection of Lipopolysaccharide (LPS) is known to cause functional impairments in the brain affecting memory and learning. One of mechanisms may be the interference with neurotrophin (NT) expression and function. In the current study we administered a single, high dose of LPS (3mg/kg, i.p.) into mice and investigated changes in brain-derived neurotrophic factor (BDNF) gene expression within 1-6 days after LPS injection. Crude synaptosomes were isolated from brain tissue and subjected to Western-blot analyses. We found transient reductions in synaptosomal proBDNF- and BDNF protein expression, with a maximal decrease at day 3 as compared to saline injected controls. The time course of reduction of BDNF mRNA in whole brain extracts parallels the decrease in protein levels in synaptosomes. LPS effects in the central nervous system (CNS) are known to crucially involve the activation of the hypothalamic-pituitary-adrenal (HPA) axis. We analysed the time course of corticotropin releasing hormone (CRH)- and proopiomelanocortin (POMC) mRNA expression. As observed for BDNF-, CRH- and POMC mRNA levels are also significantly reduced on day 3 indicating a comparable time course. These results suggest that peripheral inflammation causes a reduction of trophic supply in the brain, including BDNF at synaptic sites. The mechanisms involved could be a negative feedback of the activated HPA axis.     

No association of the Val66Met polymorphism of brain-derived neurotrophic factor (BDNF) to multiple sclerosis

Brain-derived neurotrophic factor (BDNF), a neurotrophin produced by neurons and immune cells, promotes neuronal survival and repair during development and after CNS injury. The BDNF-Val66Met polymorphism is functional and induces abnormal intracellular trafficking and decreased BDNF release. Therefore, we investigated the impact of the BDNF-Val66Met polymorphism on the susceptibility and clinical course in a case-control study of 224 multiple sclerosis (MS) Spanish patients and 177 healthy controls. We found no evidence for association to susceptibility or severity of the disease in our population. Moreover, we did not observe, in a subgroup of 12 MS patients, that the methionine substitution at position 66 in the prodomain had negative impact in the capacity to produce BDNF by peripheral blood mononuclear cells (PBMC).     

Pattern of trkB protein-like immunoreactivity in vivo and the in vitro effects of brain-derived neurotrophic factor (BDNF) on developing cochlear and vestibular neurons

The cochleo-vestibular ganglion (CVG) contains the neurons connecting the sensory epithelia of the inner ear to the cochlear and vestibular nuclei in the medulla. Expression of trkB protein-like immunoreactivity was studied in the developing CVG, using both Western blot and immunocytochemistry on tissue sections. Specific immunoreactivity was observed in the CVG from the 12th gestation day (gd) to the first postnatal week, reflecting the presence of high-affinity receptors for brain-derived neurotrophic factor (BDNF), a member of the NGF family of neurotrophins. Whole explants and dissociated cell cultures of cochlear (CG) and vestibular ganglion (VG) from mouse embryos and postnatal specimens were grown in neurotrophin-free medium to assay changes in neurite outgrowth and neuronal survival in response to the addition of physiological concentrations (0–5 ng/ml) of BDNF. Exogenous BDNF (2 ng/ml) promoted neurite outgrowth and neuronal survival in explants of both CG and VG, and the effects were stage-dependent. The onset of the response to BDNF occurred at gd 11–12. The response then reached a maximum between 14 and 18 gd and subsequently decreased, although it remained significantly present during the first postnatal week. BDNF-induced response was no longer observed in the mature cochlear and vestibular ganglion (after 30 postnatal days). The effects of BDNF on neuronal differentiation and survival were dose-dependent, starting at 0.5 ng/ml, with saturation at 2 ng/ml and half-maximal effect occurring between 1 and 1.5 ng/ml. On the basis of our results, we propose that BDNF may be physiologically involved in the control of both neuronal differentiation, and central and peripheral target-dependent neuronal death, in the CVG of embryos and early postnatal mice. BDNF may act alone or in cooperation with other neurotrophins to establish the afferent innervation of the inner ear sensory epithelium.     

Aberrant heart rate and brainstem brain-derived neurotrophic factor (BDNF) signaling in a mouse model of Huntington's disease

Huntington's disease (HD) is associated with profound autonomic dysfunction including dysregulation of cardiovascular control often preceding cognitive or motor symptoms. Brain-derived neurotrophic factor (BDNF) levels are decreased in the brains of HD patients and HD mouse models, and restoring BDNF levels prevents neuronal loss and extends survival in HD mice. We reasoned that heart rate changes in HD may be associated with altered BDNF signaling in cardiovascular control nuclei in the brainstem. Here we show that heart rate is elevated in HD (N171-82Q) mice at presymptomatic and early disease stages, and heart rate responses to restraint stress are attenuated. BDNF levels were significantly reduced in brainstem regions containing cardiovascular nuclei in HD mice and human HD patients. Central administration of BDNF restored the heart rate to control levels. Our findings establish a link between diminished BDNF expression in brainstem cardiovascular nuclei and abnormal heart rates in HD mice, and suggest a novel therapeutic target for correcting cardiovascular dysfunction in HD.     

Alterations in expression of the neurotrophic factors glial cell line-derived neurotrophic factor, ciliary neurotrophic factor and brain-derived neurotrophic factor, in the target-deprived olfactory neuroepithelium

Neuronal growth factors play an important role in the development and maintenance of the nervous system. In the olfactory system, neurogenesis and synapse formation occur not only during development but throughout life and it would be expected that growth factors play a significant role in these ongoing processes. We have examined the expression of three neurotrophic factors, glial cell line-derived neurotrophic factor, ciliary neurotrophic factor and brain-derived neurotrophic factor in the normal rat olfactory system and following synaptic target ablation (olfactory bulbectomy). We found that brain-derived neurotrophic factor immunoreactivity was confined to the horizontal basal cells of the olfactory neuroepithelium and was unaltered by bulbectomy. Glial cell line-derived neurotrophic factor immunoreactivity was present in the mature olfactory neurons and also their synaptic target cells in the olfactory bulb. Following bulbectomy, glial cell line-derived neurotrophic factor immunoreactivity was abolished from the neuroepithelium. Ciliary neurotrophic factor was present throughout the olfactory neuronal lineage with strongest immunoreactivity in the horizontal basal cells and mature olfactory neurons as well as several cell types in the olfactory bulb. Postbulbectomy, there was loss of strong ciliary neurotrophic factor immunoreactivity in olfactory neurons, however, low levels persisted in the remaining neuronal population. Horizontal basal cell immunoreactivity persisted over three months. Our results would be consistent with glial cell line-derived neurotrophic factor expression in mature olfactory neurons being dependent upon functional synaptic contact with the olfactory bulb. Alternatively, this factor may be acting as target-derived growth factor for olfactory neurons, a role in keeping with its function in spinal motoneurons and in the nigrostriatal system. Brain-derived neurotrophic factor is implicated in the trophic support of immature neurons. Ciliary neurotrophic factor is clearly important in this unique neuronal system but elucidation of its role awaits further investigation.