Alcohol-induced neuronal death in central extended amygdala and pyriform cortex during the postnatal period of the rat

Mothers who consume alcohol during pregnancy may cause a neurotoxic syndrome defined as fetal alcohol spectrum disorder (FASD) in their offspring. This disorder is characterized by reduction in brain size, cognitive deficits and emotional/social disturbances. These alterations are thought to be caused by an alcohol-induced increase in apoptosis during neurodevelopment. Little is known about neuroapoptosis in the central extended amygdala and the pyriform cortex, which are key structures in emotional/social behaviors. The goal of this study was to determine the vulnerability of neuroapoptotic alcohol effects in those areas. Rats were administered alcohol (2.5 g/kg s.c. at 0 and 2 h) or saline on postnatal day (PND) 7, 15 and 20. The Amino-cupric-silver technique was used to evaluate neurodegeneration and immunohistochemistry to detect activated caspases 3–8 and 9 at 2 h, 4, 6, 8, 12 and 24 h after drug administration. We measured blood alcohol levels each hour, from 2 to 8 h post second administration of alcohol in each of the ages studied. Results showed alcohol induced apoptotic neurodegeneration in the central extended amygdala on PND 7 and 15, and pyriform cortex on PND 7, 15 and 20. These structures showed activation of caspase 3 and 9 but not of caspase 8 suggesting that alcohol-induced apoptosis could occur by the intrinsic pathway. The pharmacokinetic differences between ages did not associate with the neurodegeneration age dependence. In conclusion, these limbic areas are damaged by alcohol, and each one has their own window of vulnerability during the postnatal period. The possible implications in emotional/social features in FASD are discussed.     

Intracerebroventricular administration of an endothelin ETB receptor agonist increases expressions of GDNF and BDNF in rat brain

Endothelins (ETs) are suggested to be involved in functional alterations of astrocytes after brain injury, including proliferation, hypertrophy and production of neurotrophic factors. In this study, effects of Ala1,3,11,15-endothelin-1 (Ala1,3,11,15-ET-1), an ETB receptor selective agonist, on neurotrophic factor production were examined in rat brain. A continuous intracerebroventricular administration of Ala1,3,11,15-ET-1 (500 pmol/day for 7 days) increased the numbers of GFAP- and vimentin-positive astrocytes in the hippocampus, caudate putamen and cerebrum. Ala1,3,11,15-ET-1 did not induce neuronal degeneration and activation of microglia/macrophage in these brain regions. The intracerebroventricular administration of Ala1,3,11,15-ET-1 for 7 days caused two- to three-fold increases in glial cell line-derived neurotrophic factors (GDNF) mRNA in the hippocampus and cerebrum. The mRNA levels of brain-derived neurotrophic factors (BDNF) in caudate putamen were increased by Ala1,3,11,15-ET-1. Expressions of nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) mRNA in these regions were not largely affected by Ala1,3,11,15-ET-1, except cerebral NGF mRNA level was increased. The Ala1,3,11,15-ET-1-induced increases in GDNF and BDNF mRNA levels were accompanied by increases in immunoreactive GDNF and BDNF. Immunohistochemical observations showed that GFAP-positive astrocytes expressed GDNF and BDNF in the brain regions of Ala1,3,11,15-ET-1-infused rats. In cultured rat astrocytes, Ala1,3,11,15-ET-1 (100 nm) increased mRNA levels of GDNF and BDNF. These results suggest that activation of brain ETB receptors induced GDNF and BDNF expression in astrocytes.     

Melatonin improves 3-nitropropionic acid induced behavioral alterations and neurotrophic factors levels

Objective

This study sought to determine whether melatonin causes changes in neurotrophic factors and it protects against the mycotoxin 3-nitropropionic acid (3-NP) in brain tissue.

Methods

Rats were given 3-NP over four consecutive days (20 mg/kg BW), while melatonin was administered over 21 days (1 mg/kg/BW), starting after the last injection of 3-NP.

Results

Rats treated with 3-NP displayed significant changes in neurotrophic factor (BDNF and GDNF) levels, together with alterations in behavior; they also displayed extensive oxidative stress and a massive neuronal damage.

Conclusions

Melatonin improved behavioral alterations, reduced oxidative damage, lowered neurotrophic factor levels and neuronal loss in 3-NP-treated rats. These results suggest that melatonin exerts a neuroprotective action.     

BDNF and GDNF serum levels in alcohol-dependent patients during withdrawal

Preclinical study results suggest that brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) modulate addictive behaviour. Therefore we investigated alterations in BDNF (81 male patients) and GDNF serum levels (52 male patients) in alcohol-dependent patients during alcohol withdrawal (day 1, 7 and 14) in comparison to healthy controls (41 male controls).     

多发性硬化、视神经脊髓炎患者血清及脑脊液中脑源性神经营养因子与胶质细胞源性神经营养因子水平

目的 探讨多发性硬化(MS)、视神经脊髓炎(NMO)患者血清及脑脊液中脑源性神经营养因子(BDNF)、胶质细胞源性神经营养因子(GDNF)水平及其神经保护作用.方法 对62例MS、NMO患者及21例对照者进行研究,患者组复发期进行扩展残疾状态量表(EDSS)评分、MRI检查及寡克隆带测定,液相芯片分析技术检测血清及脑脊液BDNF、GDNF浓度.结果 MS、NMO患者复发期血清及脑脊液BDNF(μg/L,MS患者:5.616±0.650、0.186±0.012;NMO患者6.584±0.929、0.176±0.006)、GDNF浓度(μg/L,MS患者:0.039、0.080;NMO患者0.029、0.050)与对照组(μg/L,血清:4.374±0.501、0.040;脑脊液:0.152±0.011、0.065)比较差异无统计学意义;脑脊液BDNF与GDNF浓度水平呈正相关(r=0.756,P=0.000),血清BDNF与GDNF浓度水平呈负相关(r=-0.329,P=0.018).血清及脑脊液BDNF、GDNF浓度与EDSS评分、血脑屏障指数、Delpech指数及Tourtellotte合成率无明显相关性.有或无脑萎缩的MS、NMO患者血清及腩脊液BDNF、GDNF浓度差异无统计学意义.结论 MS、NMO患者体内BDNF与GDNF水平相关,二者可能具有协同的神经保护作用.BDNF及GDNF与NMO、MS患者血脑屏障破坏及中枢神经系统内IgG合成无关,与神经功能残疾及脑萎缩的关系仍需研究.     

Effects of antipsychotics on the serum BDNF levels in schizophrenia

Brain-derived neurotrophic factor (BDNF) is active during a critical developmental period and likely influences the neuroplasticity of schizophrenia. This study longitudinally examined the effects of atypical antipsychotics on serum BDNF levels in schizophrenic patients. Specifically, this study measured serum BDNF levels in 53 patients with paranoid schizophrenia during a relapse and again 4 weeks following the administration of antipsychotic treatment (with risperidone in 32 cases, and clozapine in 21 cases). BDNF levels remained unchanged relative to study entry after 4 weeks of atypical antipsychotic treatment. However, serum BDNF was significantly increased in the subgroup receiving risperidone compared to that receiving clozapine, albeit only in the 15 male subjects and not in the 17 females. These results suggest that gender might significantly influence the antipsychotic treatment of schizophrenia from the perspective of BDNF. These findings may also indicate that the treatment with atypical antipsychotic agents differentially affects BDNF levels.     

Differential effects of ziprasidone and haloperidol on immobilization stress-induced mRNA BDNF expression in the hippocampus and neocortex of rats

Recent in vivo and in vitro experiments have demonstrated that second-generation antipsychotic drugs (SGAs) might have neuroprotective effects. Ziprasidone is a SGA that is efficacious in the treatment of schizophrenia. In this study, we sought to analyze the effects of ziprasidone on the expression of the neuroprotective protein brain-derived neurotrophic factor (BDNF) in the rat hippocampus and neocortex, with or without immobilization stress. The effect of ziprasidone (2.5 mg/kg) on the expression of BDNF mRNA was determined by in situ hybridization in tissue sections from the rat hippocampus and neocortex. Haloperidol (1.0 mg/kg) was used for comparison. Haloperidol strongly decreased the expression of BDNF mRNA in both the hippocampal and cortical regions, with or without immobilization stress (p < 0.01). In contrast, the administration of ziprasidone significantly attenuated the immobilization stress-induced decrease in BDNF mRNA expression in the rat hippocampus and neocortex (p < 0.01). Ziprasidone exhibited differential effects on BDNF mRNA expression in the rat hippocampus and neocortex. These results suggest that ziprasidone might have a neuroprotective effect by recovering stress-induced decreases in BDNF mRNA expression.     

男性慢性精神分裂症患者血清脑源性神经营养因子和胶质源性神经营养因子水平及认知功能的对照研究

目的:探讨慢性精神分裂症患者血清脑源性神经营养因子(BDNF)、胶质源性神经营养因子水平(GDNF)和神经认知功能的变化及它们之间关系。方法:入组慢性精神分裂症患者57例和正常对照39名。采用阳性与阴性症状量表(PANSS)评估患者的精神症状。使用酶联免疫吸附法检测血清BDNF、GDNF蛋白水平,采用数字划消测验、连线测验(TMT)、WMS-III空间广度测验(WMS-III SST)、定步调连续加法任务测验(PASAT)、Stroop测验、木块图评估神经认知功能。结果:患者组血清BDNF水平低于对照组,差异有统计学意义(t=9.112,P0.01),患者组血清GDNF与对照组相比差异无统计学意义(t=1.513,P0.05)。患者组数字划消测验、TMT-A、TMT-B、Stroop测验、木块图、WMS-III SST逆行分、PASAT成绩均差于对照组(P0.05)。患者组血清BDNF水平与PANSS阳性症状分、数字划消测验中的错误个数呈负相关(分别为r=-0.295,P=0.026;r=-0.262,P=0.049),血清GDNF水平与Stroop色词干扰测验分呈正相关(r=0.263,P=0.048)。结论:慢性稳定期的精神分裂症患者仍存在广泛的神经认知损害。BDNF可能是精神分裂症的一种素质性标记,可能参与了患者的注意障碍。     

Hydrophobic dipeptide Leu-Ile protects against neuronal death by inducing brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor synthesis

We investigated whether certain hydrophobic dipeptides, Leu-Ile, Leu-Pro, and Pro-Ile, which partially resemble the site on FK506 that binds to immunophilin, could stimulate glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) synthesis in cultured neurons and found only Leu-Ile to be an active dipeptide. Leu-Ile protected against the death of mesencephalic neurons from wild-type mice but not from mice lacking the BDNF or GDNF gene. Next, we examined the effects of i.p. or i.c.v. administration of Leu-Ile on BDNF and GDNF contents. Both types of administration increased the contents of BDNF and GDNF in the striatum of mice. Also, peripheral administration of Leu-Ile inhibited dopaminergic (DA) denervation caused by unilateral injection of 6-hydroxydopamine (6-OHDA) into the striatum of mice. The number of rotations following a methamphetamine challenge was lower in the Leu-Ile-treated group than in the nontreated group. Next, we compared the calcineurin activity and immunosuppressant activity of Leu-Ile with those of FK506. Leu-Ile was not inhibitory toward calcineurin cellular activity in cultured neuronal cells. Furthermore, Leu-Ile did not suppress concanavalin A (ConA)-induced synthesis/secretion of interleukin-2 by cultured spleen cells, suggesting that the immunosuppressant activity of Leu-Ile may be negligible when used as a therapeutic tool for neurodegenerative diseases.     

Brain-derived neurotrophic factor-mediated effects on mitochondrial respiratory coupling and neuroprotection share the same molecular signalling pathways

Intracerebral injection of ibotenate into mouse pups induced grey matter lesions and white matter cysts; co-administration of brain-derived neurotrophic factor (BDNF) produced a dose-dependent reduction in these lesions. In contrast, glial cell line-derived neurotrophic factor (GDNF) had no significant effect, whereas nerve growth factor (NGF) or interleukin-1β (IL-1β) resulted in dose-dependent exacerbation. The neuroprotective effects of BDNF were abolished by co-administration of anti-BDNF antibody or MEK inhibitors, or ABT-737, a BH3 mimetic and Bcl-2 antagonist. The actions of BDNF, GDNF and NGF were measured in a parallel in vitro study on the oxidative metabolism of mouse brain mitochondria. BDNF produced a concentration-dependent increase in the respiratory control index (RCI, a measure of respiratory coupling efficiency, ATP synthesis, and organelle integrity) when co-incubated with synaptosomes containing signal transduction pathways; but GDNF failed to modify RCI, and NGF had only weak effects. BDNF had no effect on pure mitochondria, and enhanced oxidation only when complex I substrates were used. The effect of BDNF was inhibited by anti-BDNF antibody, MEK inhibitors or ABT-737, and also by IL-1β, indicating that the mitochondrial effects are mediated via the same MEK-Bcl-2 pathway as the neuroprotection. The complex I inhibitor rotenone, a compound implicated in the aetiology of Parkinson's disease, inhibited both the in vitro mitochondrial and in vivo neuroprotective effects of BDNF. The ability of BDNF to modify brain metabolism and the efficiency of oxygen utilization via a MEK-Bcl-2 pathway may be an important component of the neuroprotective action observed with this neurotrophin.     

Neurochemical and behavioural effects of acute and chronic memantine administration in rats: Further support for NMDA as a new pharmacological target for the treatment of depression?

A growing body of evidence has pointed to the NMDA receptor antagonists as a potential therapeutic target for the treatment of major depression. The present study was aimed to evaluate behavioural and molecular effects of the acute and chronic treatment with memantine and imipramine in rats. To this aim, rats were acutely or chronically for 14 days once a day treated with memantine (5, 10 and 20 mg/kg) and imipramine (10, 20 and 30 mg/kg) and then subjected to the forced swimming and open-field tests. The acute treatment with memantine at all doses and imipramine at doses (20 and 30 mg/kg) reduced immobility time of rats compared to the saline group (p < 0.05), without affecting spontaneous locomotor activity and chronic treatment with memantine and imipramine, at all doses tested, reduced immobility time of rats compared to the saline group (p < 0.05), without affecting spontaneous locomotor activity. Brain-derived neurotrophic factor (BDNF) hippocampal levels were assessed in imipramine- and memantine-treated rats by ELISA sandwich assay. Interesting enough, acute administration, but not chronic administration of memantine at higher dose (20 mg/kg) increased BDNF protein levels in the rat hippocampus (p < 0.05). Finally, these findings further support the hypothesis that NMDA receptor could be a new pharmacological target for the treatment of depression.     

Peripheral nerve avulsion injuries as experimental models for adult motoneuron degeneration

We have used adult rat peripheral nerve avulsion models to evaluate the effects of neuroprotective molecules on motoneuron degeneration. The right facial nerves of adult Fischer 344 male rats were avulsed and adenoviral vectors encoding glial cell line‐derived neurotrophic factor (GDNF), brain‐derived neurotrophic factor (BDNF), transforming growth factor‐β2 (TGFβ2), and growth inhibitory factor (GIF) were injected into the facial canal. The treatment with the vectors significantly prevented the loss of lesioned facial motoneurons, improved choline acetyltransferase (ChAT) immunoreactivity and suppressed the induction of nitric oxide synthase activity in these neurons. In separate experiments, animals were orally administered a solution of a neuroprotective compound T‐588 after avulsion. Both free oral administration and oral tube administration of T‐588 improved the survival of injured motoneurons and ameliorated their ChAT immunoreactivity. These results indicate that the gene transfer of GDNF, BDNF, TGFβ2, and GIF and oral administration of T‐588 may prevent the degeneration of motoneurons in adult humans with motoneuron injury and motor neuron diseases.     

Higher levels of brain derived neurotrophic factor but similar nerve growth factor in human milk in women with preeclampsia

Children born to mothers with preeclampsia have consistently been suggested to be at risk for cognitive and behavioral disorders in later life. Breastfeeding is said to be associated with better neurodevelopment outcomes. Our earlier studies indicated higher levels of docosahexaenoic acid (DHA) in human milk in women with preeclampsia. DHA is known to regulate the expression of neurotrophins and together they play a vital role in neurodevelopment and cognitive performance. The present study examines the levels of maternal plasma and milk neurotrophins [(nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF)] in women with preeclampsia and compares them with normotensive women who served as controls. Singleton pregnant women diagnosed with preeclampsia (n = 72) and controls (n = 102) were recruited for this study from Bharati Hospital, Pune. Plasma and milk samples were analyzed for NGF and BDNF levels using the Emax Immuno Assay System using promega kits. Maternal plasma NGF and BDNF levels were lower (p < 0.01 for both) in women with preeclampsia as compared to the control women. Milk NGF levels were similar while milk BDNF levels were higher (p < 0.05) in the preeclampsia group as compared to controls. Plasma NGF levels were positively correlated with milk NGF levels in the control group. Our results indicate the differential regulation of milk NGF and BDNF levels in women with preeclampsia. The present study suggests a role for both NGF and BDNF in human milk for postnatal brain development. Further studies need to examine the associations of DHA and BDNF in human milk with cognition at later ages.     

The brain-derived neurotrophic factor (BDNF) polymorphism Val66Met is associated with neither serum BDNF level nor response to selective serotonin reuptake inhibitors in depressed Japanese patients

Background

We investigated the relationship between a brain-derived neurotrophic factor (BDNF) polymorphism (Val66Met) and the clinical response of patients with major depressive disorder to selective serotonin reuptake inhibitors (SSRIs; here, paroxetine and sertraline). In addition, serum BDNF levels in these patients were considered together with the clinical response.

Methods

A total of 132 patients who met the DSM-IV criteria for major depressive disorder were enrolled in the study. 54 of these patients were male and 78 were female (age range, 20-74 years; mean ± S.D., 51 ± 15). The patients' clinical improvement was evaluated using the 17-item Hamilton Rating Scale for Depression (HAMD-17) before (T0) and at 8 weeks after the administration of SSRI treatment (T8). Patients with at least a 50% decrease in the HAMD-17 score were classified as responders.

Results

No correlation was observed between the BDNF Val66Met polymorphism and response to SSRIs or between the BDNF Val66Met polymorphism and serum BDNF levels at T0. An inverse correlation was found between serum BDNF levels and HAMD-17 scores at T0.

Conclusions

These results suggest that the BDNF Val66Met polymorphism is independent of both the response to SSRI treatment and serum BDNF levels. The findings in the present study reconfirm that the serum BDNF level is a state biomarker for depression.     

The influence of N-desmethylclozapine and clozapine on recognition memory and BDNF expression in hippocampus

Clozapine, which is the most effective treatment option for treatment-refractory schizophrenia, has been reported to have both positive and negative effects on specific cognitive symptoms in patients with schizophrenia and in animal models of cognition. Clozapine has a major metabolite, N-desmethylclozapine (NDMC), which has been suggested to be more effective than clozapine itself to improve cognition. Enhancement of brain derived neurotrophic factor (BDNF) expression in the hippocampus has been proposed to contribute to the cognitive-enhancing effects of antipsychotic drugs. The aims of this study were to investigate the change in short and long term memory as assessed by the novel object recognition (NOR) test and BDNF expression in hippocampus produced by an acute hypoglutamatergic model of memory impairment in schizophrenia induced by administration of the NMDA receptor non-competitive antagonist, MK-801 and the ability of clozapine and NDMC to prevent the deleterious effects of MK-801. Both short (1 h) and long-term (24 h) memory were impaired in MK-801 (0.1 mg/kg) - and clozapine (5 mg/kg)-, but not NDMC (5 mg/kg)-treated rats. Neither NDMC (5 mg/kg) nor clozapine (5 mg/kg) reversed the effect of MK-801. Western blotting studies showed that BDNF levels in hippocampus were not different in rats administered MK-801 alone, clozapine or NDMC alone. These results show that in this model clozapine affects memory negatively, while NDMC does not. The absence of impairment of NOR with NDMC is consistent with previous evidence that it has a more benign effect on cognition than does the parent compound, and may support the efforts to study its effects on other cognitive functions. These findings do not provide any support for the role of BDNF in the MK-801-induced impairment in NOR or for differences between clozapine and NDMC.     

Serum brain-derived neurotrophic factor predicts responses to escitalopram in chronic posttraumatic stress disorder

Introduction

Some studies have found that antidepressants increase serum brain-derived neurotrophic factor (BDNF) levels in patients with major depression and the expression of BDNF mRNA in limbic structures of rats.

Objectives

This study addressed whether the SSRI escitalopram increases serum BDNF levels in subjects with PTSD and whether BDNF levels are associated with treatment response.

Methods

Medically healthy male subjects (N = 16) with chronic PTSD completed a 12 week open-label trial of flexible dose (5–20 mg/day) escitalopram monotherapy. BDNF levels were obtained at baseline, and at weeks 4, 8 and 12.

Results

PTSD symptoms significantly declined over the course of the 12 week escitalopram treatment. Despite a substantial improvement in PTSD symptoms, there was virtually no change in BDNF levels over time. Nevertheless, mean BDNF levels across the trial were strongly correlated with the slope of PTSD symptoms over the 12 weeks (r = 0.58, p = 0.018). Lower mean BDNF was associated with a greater decrease in PTSD symptoms over the course of the trial.

Conclusions

PTSD subjects with low BDNF levels demonstrated the largest treatment response from an agent with putative neurotrophic effects.     

Early life stress decreases hippocampal BDNF content and exacerbates recognition memory deficits induced by repeated D-amphetamine exposure

Adverse experiences early in life may have profound influences on brain development, for example, determining alterations in response to psychostimulant drugs, an increased risk of developing a substance abuse disorder, and individual differences in the vulnerability to neuropsychiatric disorders later in life. Here, we investigated the effects of exposure to an early adverse life event, maternal deprivation, combined with repeated d-amphetamine (AMPH) administration in adulthood, on recognition memory and brain-derived neurotrophic factor (BDNF) levels in rats’ brain and serum. Rats were exposed to one of the following maternal rearing conditions from postnatal days 1 to 14: non-deprived (ND) or deprived (D). In adulthood, both groups received injections of saline (SAL) or AMPH (2.0 mg/kg, i.p.) for 7 days. In Experiment I (performed 24 h after the last AMPH injection), AMPH induced long-term memory (LTM) impairments in ND and D groups. The D + AMPH group also presented short-term memory (STM) impairments, indicating that the effects of AMPH on memory were more pronounced when the animals where maternally deprived. The group exposed to D + SAL (SAL) showed only LTM impairments. In Experiment II (performed 8 days after the last injection), AMPH detrimental effects on memory persisted in ND and D groups. BDNF levels were decreased in the hippocampus of D + SAL rats. In conclusion, AMPH produces severe and persistent recognition memory impairments that were more pronounced when the animals were maternally deprived, suggesting that an early adverse life event may increase the vulnerability of cognitive function to exposure to a psychostimulant later in life.     

Dopamine D3 receptor-preferring agonists induce neurotrophic effects on mesencephalic dopamine neurons

Anti-parkinsonian agents, pramipexole (PPX) and ropinirole (ROP), have been reported to possess neuroprotective properties, both in vitro and in vivo. The mechanisms underlying neuroprotection afforded by the D3-preferring receptor agonists remain poorly understood. The present study demonstrates that incubation of primary mesencephalic cultures with PPX and ROP or the conditioned medium from PPX- or ROP-treated primary cultures induced a marked increase in the number of dopamine (DA) neurons in the cultures. Similar effects can be observed after incubating with the conditioned medium derived from PPX- and ROP-treated substantia nigra astroglia. Meanwhile, PPX and ROP can protect the primary cells from insult of 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). Furthermore, the neurotrophic effects of PPX and ROP on mesencephalic dopamine neurons could be significantly blocked by D3 receptor antagonist, but not by D2 receptor antagonist. Moreover, we found that the levels of glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) in the conditioned medium of mesencephalic cultures treated with PPX and ROP were significantly increased. Blocking GDNF and BDNF with the neutralizing antibodies, the neurotrophic effects of PPX and ROP were greatly diminished. These results suggest that D3 dopamine receptor-preferring agonists, PPX and ROP, exert neurotrophic effects on cultured DA neurons by modulating the production of endogenous GDNF and BDNF, which may participate in their neuroprotection.     

Reduced platelet BDNF level in patients with major depression

Serum and plasma brain-derived neurotrophic factor (BDNF) levels as well as brain BDNF have previously been shown to be decreased in patients with major depressive disorder (MDD). We explored whether platelet BDNF levels, circulating stored BDNF, would be lower in MDD patients than in normal controls. BDNF levels were examined in platelet-rich plasma (PRP) and platelet-poor plasma (PPP) in 20 hospitalized non-suicidal MDD patients, 20 recent-suicidal MDD patients, and 20 normal controls. Platelet BDNF content was calculated by subtracting PPP BDNF level from PRP BDNF level, and dividing the result by the total platelet count, and it was expressed as pg/10⁶ platelets. Individuals were evaluated using a Structured Clinical Interview for DSM-IV and a Hamilton Depression Rating Scale. Platelet BDNF contents were significantly lower in non-suicidal patients (3.09 ± 2.53 pg/10⁶ platelets) and recent-suicidal MDD patients (3.16 ± 1.99 pg/10⁶ platelets) than in healthy controls (6.17 ± 2.64 pg/10⁶ platelets) (p < 0.01). However, platelet BDNF contents had no significant differences between non-suicidal and recent-suicidal patients. PRP BDNF levels were also significantly lower in non-suicidal and suicidal MDD patients than in healthy controls (p = 0.029), while PPP BDNF had no significant difference between 3 groups (p = 0.971). Our findings suggest that there is a decrease in the platelet BDNF of patients with major depression. Reduced platelet BDNF contents as circulating stored BDNF could be associated with lower serum BDNF level in patients with major depression.     

Immunosuppressive (FK506) and non-immunosuppressive (GPI1046) immunophilin ligands activate neurotrophic factors in the mouse brain

Based on the fact that several recent reports have indicated that non-immunosuppressive immunophilin ligands (IPLs) can activate neurite outgrowth or nerve regeneration, we investigated the neurotrophic factor-activating abilities of IPLs in vivo in order to clarify the molecular basis of neurotrophic-like activity. Both FK506 (an immunosuppressive IPL) and GPI1046 (a non-immunosuppressive IPL) significantly increased glial cell line-derived neurotrophic factor (GDNF) content in the substantia nigra. In addition, FK506 increased striatal brain-derived neurotrophic factor (BDNF) content significantly. Thus, our present results suggest that the molecular basis of IPL-induced neurotrophic-like activity may be dependent on GDNF and/or BDNF activation.