Neurotrophins induce BDNF expression through the glutamate receptor pathway in neocortical neurons

Neurotrophins jointly exert various functions in the nervous system, including neuronal differentiation, survival, and regulation of synaptic plasticity. However, the functional interactions of neurotrophins or mechanisms through which neurotrophins regulate each other are still not clear. In the present study, brain-derived neurotrophic factor (BDNF) mRNA expression is induced by neurotrophin-4/5 (NT-4/5) and by BDNF itself in neocortical neurons. K252a, a specific tyrosine kinase (Trk) inhibitor, completely suppresses BDNF- and NT-4/5-enhanced BDNF mRNA expression. NT-4/5 significantly augments BDNF protein production, which is also reversed by K252a. When neurons are incubated with neurotrophin-3 (NT-3) or nerve growth factor (NGF), there are no significant changes in BDNF mRNA or protein expression. Interestingly, the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor blocker 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) or the N-methyl-D-aspartate (NMDA) receptor blocker AP-5 completely suppresses NT-4/5-enhanced BDNF protein production, while tetrodotoxin (TTX) only suppresses NT-4/5-enhanced BDNF production by 50%. Additionally, the mitogen activated protein (MAP) kinase inhibitor PD98059 enhances BDNF-induced glutamate receptor-1 (GluR1) protein expression, but a phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 strongly reduces BDNF-induced GluR1 protein expression. Taken together, glutamate receptors are important for the regulation of BDNF expression by neurotrophins, and MAP and PI3K kinases differentially modulate AMPA receptor expression in the cortical neurons.     

Up-regulation of BDNF in Astrocytes by TNF-α: A Case for the Neuroprotective Role of Cytokine

Tumor necrosis factor-alpha (TNF-α) is widely known to be involved in physiological and pathophysiological processes of the brain where this proinflammatory cytokine is implicated with regulation of inflammatory and survival components. We report that TNF-α up-regulates exon-IV-bdnf mRNA and brain-derived neurotrophic factor (BDNF) protein in primary astrocytes. The BDNF protein was detectable both in cellular lysate and in the extracellular medium. Activation of NF-κB by TNF-α and inhibition of TNF-α-induced BDNF expression by Δp65 (a dominant-negative mutant) and NEMO-binding domain peptide (an inhibitor of NF-κB) suggests that TNF-α induces BDNF expression through the activation of NF-κB. Similarly, TNF-α induced the activation of C/EBPβ and the expression of BDNF was sensitive to overexpression of ΔC/EBPβ (a dominant-negative mutant) and ETO (an inhibitor of C/EBPβ). Among three MAP kinases, TNF-α-induced BDNF up-regulation was sensitive only to inhibitors of ERK MAP kinase. However, the ERK MAP kinase pathway was coupled to activation of C/EBPβ but not NF-κB. Taken together, this study identifies a novel property of TNF-α in inducing the expression of BDNF via NF-κB and C/EBPβ in astrocytes that may be responsible for neurotrophic activity of the cytokine.     

Up-Regulation of Neurotrophic Factors by Cinnamon and its Metabolite Sodium Benzoate: Therapeutic Implications for Neurodegenerative Disorders

This study underlines the importance of cinnamon, a widely-used food spice and flavoring material, and its metabolite sodium benzoate (NaB), a widely-used food preservative and a FDA-approved drug against urea cycle disorders in humans, in increasing the levels of neurotrophic factors [e.g., brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3)] in the CNS. NaB, but not sodium formate (NaFO), dose-dependently induced the expression of BDNF and NT-3 in primary human neurons and astrocytes. Interestingly, oral administration of ground cinnamon increased the level of NaB in serum and brain and upregulated the levels of these neurotrophic factors in vivo in mouse CNS. Accordingly, oral feeding of NaB, but not NaFO, also increased the level of these neurotrophic factors in vivo in the CNS of mice. NaB induced the activation of protein kinase A (PKA), but not protein kinase C (PKC), and H-89, an inhibitor of PKA, abrogated NaB-induced increase in neurotrophic factors. Furthermore, activation of cAMP response element binding (CREB) protein, but not NF-κB, by NaB, abrogation of NaB-induced expression of neurotrophic factors by siRNA knockdown of CREB and the recruitment of CREB and CREB-binding protein to the BDNF promoter by NaB suggest that NaB exerts its neurotrophic effect through the activation of CREB. Accordingly, cinnamon feeding also increased the activity of PKA and the level of phospho-CREB in vivo in the CNS. These results highlight a novel neutrophic property of cinnamon and its metabolite NaB via PKA – CREB pathway, which may be of benefit for various neurodegenerative disorders.     

An efficient neuron-astrocyte differentiation protocol from human embryonic stem cell-derived neural progenitors to assess chemical-induced developmental neurotoxicity

Human embryonic stem cell neuronal differentiation models provide promising in vitro tools for the prediction of developmental neurotoxicity of chemicals. Such models mimic essential elements of human relevant neuronal development, including the differentiation of a variety of brain cell types and their neuronal network formation as evidenced by specific gene and protein biomarkers. However, the reproducibility and lengthy culture duration of cell models present drawbacks and delay regulatory implementation. Here we present a relatively short and robust protocol to differentiate H9-derived neural progenitor cells (NPCs) into a neuron-astrocyte co-culture. When frozen-stored NPCs were re-cultured and induced into neuron-astrocyte differentiation, they showed gene- and protein expression typical for these cells, and most notably they exhibited spontaneous electrical activity within three days of culture as measured by a multi-well micro-electrode array. Modulating the ratio of astrocytes and neurons through different growth factors including glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), and ciliary neurotrophic factor (CNTF) did not compromise the ability to develop spontaneous electrical activity. This robust neuronal differentiation model may serve as a functional component of a testing strategy for unravelling mechanisms of developmental neurotoxicity.     

阿戈美拉汀在缺血性脑卒中后抑郁中的应用

目的：观察阿戈美拉汀治疗缺血性脑卒中伴抑郁的临床疗效及对神经细胞因子的影响。方法：111例患者随机分为对照组55例和观察组56例，两组均予卒中常规治疗，对照组加服艾司西酞普兰，观察组加服阿戈美拉汀。均治疗6周。分别采用HAMD量表、NIHSS量表、PSQI量表评价抑郁、神经功能缺损和睡眠障碍，多导睡眠监测仪记录睡眠参数，ELISA法测定血清脑源性神经营养因子（BDNF）、胶质细胞源性神经营养因子（GDNF）、神经生长因子（NGF）、睫状神经营养因子（CNTF）含量，记录不良反应。结果：治疗3周，观察组抗抑郁有效率为58.9%，高于对照组38.2%。与对照组相比，治疗3周和治疗6周时，观察组PSQI量表评分均明显降低；治疗6周时，观察组睡眠潜伏期（SL）、觉醒总时间（AT）缩短，总睡眠时间（TST）、睡眠效率（SE），血清BDNF、CNTF含量明显增加（P<0.05）。其余指标组间相近（P>0.05）。结论：阿戈美拉汀对缺血性脑卒中伴抑郁具有良好治疗作用，其机制可能与提高血清神经细胞因子含量有关。     

The preclinical rationale for the use of insulin-like growth factor-I in amyotrophic lateral sclerosis

This review details the general physiology, biochemistry and molecular biology of insulin-like growth factor I (IGF-I), a pleiotropic factor, and the only one to date showing beneficial effects in a prototypic neurodegenerative disease, amyotrophic lateral sclerosis (ALS). The preclinical rationale for IGF-I use in treating patients with ALS stems from the fact that this molecule has endocrine, paracrine and autocrine effects on cells and acts through a receptor tyrosine kinase that is structurally and functionally similar to the insulin receptor. What has come to be known as the IGF signaling system is reviewed within the context of differences as well as similarities of IGF-I's actions within the peripheral and central nervous systems compared with other tissues. This signaling pathway is complex, involving several cell surface receptors, circulating and bound binding proteins and specific proteases that recognize and cleave individual binding proteins that serves to finely adjust the cellular responses to IGF-I. In order to explain why this trophic factor, unlike ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF), was found to have efficacy in large-scale clinical trials in ALS patients, evidence is offered that IGF-I affects all components of the motor unit: spinal cord motor neuron, axon, neuromuscular synapse and muscle fiber. A model is presented that shows life and death signals on motor neurons, with the serine protease, thrombin, representing an extracellular death signal and IGF-I, a potent life signal, on such cells.     

普拉克索和罗匹尼罗对体外培养的多巴胺神经元的神经营养作用

目的 :探讨新型选择性多巴胺D3受体激动剂普拉克索和罗匹尼罗对多巴胺神经元的神经营养作用及其机制。方法 :在大鼠的腹侧中脑细胞和不同部位星形胶质细胞培养基中加入普拉克索和罗匹尼罗刺激 ,观察药物对多巴胺神经元存活的影响。结果 :药物直接作用或从黑质区星形胶质细胞培养基中提取的条件培养液均可使酪氨酸羟化酶 (TH )阳性神经元数量增加 ,同时培养液中脑源性神经营养因子 (BDNF)和胶质细胞源性神经营养因子(GDNF)含量增加。而其他脑区的星形胶质细胞不能产生类似作用。结论 :普拉克索和罗匹尼罗对多巴胺神经元具有神经营养作用 ,这可能是由于其使特定区域星形胶质细胞产生并分泌了神经营养因子。     

Ciglitazone induces caspase-independent apoptosis via p38-dependent AIF nuclear translocation in renal epithelial cells

Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists have been reported to induce apoptosis in a variety of cell types including renal proximal epithelial cells. However, the underlying mechanism of cell death induced by PPARgamma agonists has not been clearly defined in renal proximal tubular cells. This study was therefore undertaken to determine the mechanism by which ciglitazone, a synthetic PPARgamma agonist, induces apoptosis in opossum kidney (OK) cells, an established renal epithelial cell line. Ciglitazone treatment induced apoptotic cell death in a dose- and time-dependent manner. Ciglitazone caused a transient activation of ERK and sustained activation of p38 MAP kinase. Ciglitazone-mediated cell death was attenuated by the p38 inhibitor SB203580 and transfection of dominant-negative form of p38, but not by the MEK inhibitor U0126, indicating that p38 MAP kinase activation is involved in the ciglitazone-induced cell death. Although ciglitazone-induced caspase-3 activation, the ciglitazone-mediated cell death was not affected by the caspase-3 inhibitor DEVD-CHO. Ciglitazone-induced mitochondrial membrane depolarization and apoptosis-inducing factor (AIF) nuclear translocation and these effects were prevented by the p38 inhibitor. These results suggest that ciglitazone induces caspase-independent apoptosis through p38 MAP kinase-dependent AIF nuclear translocation in OK renal epithelial cells.     

复合神经营养因子应用于大鼠视神经损伤的研究

目的观察玻璃体腔注射复合神经营养因子(睫状神经营养因子,CNTF和脑源性神经营养因子,BDNF)对大鼠视神经损伤后视网膜神经节细胞存活的作用。方法60只健康成年大鼠、体重200～225g、雌性,随机分为对照组、CNTF治疗组、BDNF治疗组及复合神经营养因子(CNTF+BDNF)治疗组。各组又分为7、14、21d3个时间组,每组5只大鼠,每只动物进行单眼实验,另外一眼为正常对照。荧光金逆行标记视网膜神经节细胞(RGCs),7d后做成视神经损伤模型。4组术后分别向玻璃体腔内注射生理盐水、CNTF、BDNF、CNTF+BDNF。按视神经损伤后不同时间点,分别将动物灌注固定。做全视网膜铺片,荧光显微镜下观察,在每张视网膜距视乳头1mm部位随机取4个视野拍片,对每个视野中标记的RGCs进行计数,求平均值,计算视神经损伤后玻璃体腔内注射不同药物、不同时间所剩余的RGCs数。结果视神经夹伤后各组RGCs随时间推移逐渐减少。与对照组相比,CNTF治疗组、BDNF治疗组及CNTF+BDNF治疗组7、14、21d各组RGCs数均明显多于对照组(P<0.01),且CNTF+BDNF治疗组RGCs数亦明显多于单独应用一种神经营养因子的CNTF治疗组、BDNF治疗组(P<0.01)。结论在对大鼠视神经损伤的治疗中,应用CNTF+BDNF明显优于单独应用一种神经营养因子(CNTF或BDNF)。     

Effects of [6]-shogaol on cholinergic signaling in HT22 cells following neuronal damage induced by hydrogen peroxide

Cholinergic neurons play a major role in memory and attention. The dysfunction and death of these neurons, especially in the hippocampus, are thought to contribute to the pathophysiology of memory deficits associated with Alzheimer’s disease (AD). Therefore, studying the cholinergic properties and cell survival may help in treating this disease. We investigated the possible effects of [6]-shogaol on cholinergic signaling in HT22 hippocampal neuronal cells. HT22 cells express essential cholinergic markers, including choline acetyltransferase (ChAT) and choline transporter (ChTp). HT22 cells treated with H₂O₂ for 3 h showed an increase in ROS production (35%). These features were partly recovered by [6]-shogaol. Treating H₂O₂-treated HT22 cells with [6]-shogaol markedly increased the expression of ChAT and ChTp, an effect similar to that of brain-derived neurotrophic factor (BDNF). Furthermore, K-252a, an inhibitor of the BDNF receptor Trk B, attenuated the effects of both [6]-shogaol and BDNF. These data suggest that [6]-shogaol protects neurons by increasing ChAT and ChTp expression through a BDNF increase and thus may be useful for treating neurodegenerative diseases.     

阻塞性睡眠呼吸暂停低通气综合征老年患者神经营养因子水平与认知功能的相关性

目的 探讨阻塞性睡眠呼吸暂停低通气综合征(OSAHS)患者血清神经营养因子水平的变化及其与认知功能间的相关性。方法 按顺序纳入该院2013年5月至2014年9月收治的患者77例,参照呼吸暂停低通气指数(AHI)标准分为轻度OSAHS组25例、中度OSAHS组25例和重度OSAHS组27例;同时选择25例体检者作为健康对照组;分别进行多导睡眠图(PSG)监测;采用蒙特利尔认知评估量表(MoCA)和简易智能状态量表(MMSE)对各组的认知功能进行评价;并检测血清神经生长因子(NGF),脑源性神经营养因子(BDNF),胶质细胞源性神经营养因子(GDNF)和睫状神经营养因子(CNTF)水平。分析以上参数间的相关性。结果与对照组比较,轻、中和重度OSAHS组患者的AHI、氧减指数(ODI)、呼吸相关微觉醒指数(RI)和脉氧饱和度低于90％的时间占总睡眠时间的百分比(TS90％)均明显升高(P＜0.01),且重度组较轻和中度组升高更明显(P＜0.01);而重度组患者的最低脉氧饱和度(LSaO₂)和平均脉氧饱和度(MSaO₂)较对照组明显降低(P＜0.01);与对照组比较,重度OSAHS组患者的MoCA、MMSE评分显著降低(P＜0.01);与轻、中度OSAHS组相比,重度OSAHS组MoCA评分显著降低(P＜0.01)。与对照组比较,轻、中和重度OSAHS组患者血清神经营养因子水平均减少;而重度OSAHS组患者血清营养因子较对照组、轻和中度OSAHS组患者明显减少,比较差异有统计学意义(P＜0.01)。血清营养因子水平与睡眠呼吸记录指标AHI、ODI、RI 和TS90％呈负相关,而与最低SaO₂和平均SaO₂呈正相关。血清营养因子水平与认知功能指标MoCA 和MMSE均呈正相关。结论 血清神经营养因子水平是反映OSAHS患者的重要指标,且与其认知功能障碍密切相关。     

Propofol attenuates oxidative stress-induced PC12 cell injury via p38 MAP kinase dependent pathway

Aim： To investigate the neuroprotective effect of propofol and its intracellular mechanism on neurons in vitro. Methods： Cell viability was determined with 3-（4, 5-dimethylthiazol-2-yl）-2,5-diphenyl tetrazolium bromide reduction. Apoptotic cell death was determined by Hoechst 33258 staining and a fluorescence-activated cell sorter. The caspase-3 activity was measured by fluorometric assay. Mitogenactivated protein （MAP） kinase phosphorylation was detected with Western blotting. Results： The pretreatment of rat pheochromocytoma cell line PC 12 with propofol （1-10 μmol/L） resulted in a significant recovery from hydrogen peroxide （H2O2）-induced cell death and the inhibition of H2O2 induced caspase-3 activation and PC12 cell apoptosis. Propofol inhibited the H2O2-induced p38 MAP kinase, but not c-Jun N-terminal kinase or extracellular signal-regulated kinase 1 and 2 activations. Conclusion： Propofol might attenuate H2O2-induced PC 12 cell death through the inhibition of signaling pathways mediated by the p38 MAP kinase.     

NVP-AAM077和Ro25-6981对全脑缺血小鼠海马神经元损伤及BDNF表达的影响

目的探讨N-甲基-D-天冬氨酸受体(NMDA)亚基NR2A和NR2B特异性拮抗剂对脑缺血/再灌注后海马CA1区神经元损伤的不同影响及其可能机制。方法制作三动脉阻断(3-VO)小鼠全脑缺血模型,小鼠随机分为假手术组、脑缺血/再灌注(I/R)对照组、NVP-AAM077(NVP)干预组和Ro25-6981(Ro)干预组;应用Fluoro-JadeB(F-JB)和Nissl染色检测海马神经元变性死亡和存活情况,Western blot对脑源性神经生长因子(BDNF)蛋白表达水平进行定量分析。结果①小鼠全脑缺血12min/再灌注3d后,海马CA1区出现选择性迟发性神经元死亡,NVP干预组增加了缺血所致的海马神经元死亡(P<0.05),而Ro干预组CA1区神经元存活数量明显多于缺血/再灌注组(P<0.01);②NVP干预能明显下调缺血/再灌注所致的海马组织BDNF蛋白表达升高(P<0.01),而Ro干预能明显上调BDNF蛋白的表达(P<0.05)。结论 NMDA受体亚基NR2A和NR2B在小鼠脑缺血/再灌注损伤中具有不同的作用,其机制可能与调节BDNF表达改变有关。     

Regulation of BDNF expression in primary neuron culture by LY392098, a novel AMPA receptor potentiator

The effects of a novel AMPA receptor potentiator (LY392098) on the expression of brain-derived neurotrophic factor (BDNF) were examined in primary neuron culture. The addition of either AMPA or LY392098 to cortical neurons elicited a time and concentration dependent increase in mRNA encoding BDNF. Moreover, co-addition of subeffective concentrations of AMPA (1 μM) and LY392098 (1 μM) resulted in dramatic increases in both BDNF mRNA (>25-fold) and protein (7-fold) levels, whilst no changes in either NT-3 or NT-4 mRNA were detected. More modest (1.5–2.5-fold) elevations in BDNF mRNA and protein expression were also produced by combinations of AMPA and LY392098 in cerebellar granule cell neurons. In contrast, AMPA and LY392098, either alone or in combination, did not elevate BDNF mRNA levels in primary astroglial cultures. Maximum elevations in BDNF mRNA and protein were produced by 6–12 h of AMPA receptor activation 1–3 h of AMPA receptor activation were required to elevate BDNF mRNA levels. AMPA receptor-mediated increases in BDNF mRNA and protein were abolished by the AMPA antagonist, NBQX, but were unaffected by the NMDA antagonist, MK-801. In cortical neuron cultures, activation of both L-type Ca⁺² channels and mitogen-activated protein (MAP) kinases contribute to AMPA receptor-mediated increases in BDNF mRNA. The ability of LY392098 to increase the expression of BDNF in primary neuron culture indicates this and related biarylpropylsulfonamides may be useful in the treatment of neuropsychiatric disorders.     

Glycans and glycan-binding proteins in brain: galectin-1-induced expression of neurotrophic factors in astrocytes

Astrocytes are a major cell type in the central nervous system (CNS). They are considered to act in cooperation with neurons and other glial cells and to participate in the development and maintenance of functions of the CNS. Immature astrocytes possess a polygonal shape and have no processes, and continue to proliferate, while mature astrocytes have a stellate cell morphology, increased glial fibrillary acidic protein expression, and proliferate slowly. Stellate astrocytes, which immediately appear at the site of brain lesions by ischemia or other brain injuries, are thought to produce several neurotrophic factors to protect neurons from delayed post-lesion death. Previously we reported that galectin-1, a member of the family of beta-galactoside-binding proteins, induced astrocyte differentiation, and the differentiated astrocytes greatly enhanced their production of brain-derived neurotrophic factor (BDNF). BDNF is known to promote neuronal survival, guide axonal pathfinding, and participate in activity-dependent synaptic plasticity during development. The effect of galectin-1 is astrocyte-specific and does not have any effect on neurons. Prevention of neuronal loss during CNS injuries is important to maintain brain function. Induction of neuroprotective factors in astrocytes by an endogenous mammalian lectin may be a new mechanism for preventing neuronal loss after brain injury, and may be useful for the treatment of neurodegenerative disorders.     

Brain-derived neurotrophic factor prevents phencyclidine-induced apoptosis in developing brain by parallel activation of both the ERK and PI-3K/Akt pathways

Phencyclidine is an N-methyl d-aspartate receptor (NMDAR) blocker that has been reported to induce neuronal apoptosis during development and schizophrenia-like behaviors in rats later in life. Brain-derived neurotrophic factor (BDNF) has been shown to prevent neuronal death caused by NMDAR blockade, but the precise mechanism is unknown. This study examined the role of the phosphatidylinositol-3 kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) pathways in BDNF protection of PCP-induced apoptosis in corticostriatal organotypic cultures. It was observed that BDNF inhibited PCP-induced apoptosis in a concentration-dependent fashion. BDNF effectively prevented PCP-induced inhibition of the ERK and PI-3K/Akt pathways and suppressed GSK-3β activation. Blockade of either PI-3K/Akt or ERK activation abolished BDNF protection. Western blot analysis revealed that the PI-3K inhibitor LY294002 prevented the stimulating effect of BDNF on the PI-3K/Akt pathway, but had no effect on the ERK pathway. Similarly, the ERK inhibitor PD98059 prevented the stimulating effect of BDNF on the ERK pathway, but not the PI-3K/Akt pathway. Co-application of LY294002 and PD98059 had no additional effect on BDNF-evoked activation of Akt or ERK. However, concurrent exposure to PD98059 and LY294002 caused much greater inhibition of BDNF-evoked phosphorylation of GSK-3β at serine 9 than did LY294002 alone. Finally, either BDNF or GSK-3β inhibition prevented PCP-induced suppression of cyclic-AMP response element binding protein (CREB) phosphorylation. These data demonstrate that the protective effect of BDNF against PCP-induced apoptosis is mediated by parallel activation of the PI-3K/Akt and ERK pathways, most likely involves inhibition of GSK-3β and activation of CREB.     

Caffeic acid phenethyl ester protects nigral dopaminergic neurons via dual mechanisms involving haem oxygenase-1 and brain-derived neurotrophic factor

BACKGROUND AND PURPOSE

Caffeic acid phenethyl ester (CAPE) is a component of honey bee propolis that can induce expression of haem oxygenase-1 (HO-1). Because HO-1 induction has been suggested to protect dopaminergic neurons in the substantia nigra, we examined the effect of CAPE in experimental models of dopaminergic neurodegeneration.

EXPERIMENTAL APPROACH

Neuroprotective effect of CAPE was investigated in rat organotypic midbrain slice cultures and in vivo, using a mouse model of dopaminergic neurodegeneration induced by intranigral injection of LPS and intrastriatal injection of 6-hydroxydopamine.

KEY RESULTS

CAPE protected dopaminergic neurons in slice cultures from IFN-γ/LPS-induced injury. The effect of CAPE was inhibited by zinc protoporphyrin IX, an HO-1 inhibitor, and by neutralizing antibody against brain-derived neurotrophic factor (BDNF). A p38 MAPK inhibitor SB203580 prevented activation of NF-E2-related factor 2, attenuated increased expression of HO-1 and BDNF, and blocked the neuroprotective actions of CAPE. In the LPS-injected mouse model, daily intraperitoneal administration of CAPE protected dopaminergic neurons, up-regulated HO-1 and BDNF, and reduced the increase of activated microglia/macrophages. Neuroprotective effects of CAPE against LPS-induced injury was prevented by zinc protoporphyrin IX or anti-BDNF antibody. CAPE protected dopaminergic neurons and alleviated methamphetamine-induced rotational behaviour also in 6-hydroxydopamine hemiparkinsonian mice.

CONCLUSION AND IMPLICATIONS

CAPE is a novel type of neuroprotective agent whose actions are mediated by both HO-1 and BDNF. These findings may provide novel clues to develop neuroprotective agents for treatment of neurodegenerative disorders.     

Neurotrophic factors: from physiology to pharmacology?

The recent cloning of new members of the nerve growth factor (NGF) family, namely brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), as well as the ciliary neurotrophic factor (CNTF) has greatly expanded our knowledge of the structural properties and neurotrophic activities of these proteins. Elucidation of their developmental and topographical expression and associated receptors in both the central nervous system (CNS) and peripheral nervous system (PNS) is proceeding at a brisk pace, leading us to propose a potential pharmacological use of these proteins. This possibility will ultimately rely upon a more complete understanding of the roles of these trophic factors in nervous system physiology and pathology.     

Zinc treatment induces cortical brain-derived neurotrophic factor gene expression

Most of antidepressants induce expression of the gene coding for brain-derived neurotrophic factor (BDNF) in the hippocampal/cortical neurons. Recent data indicate antidepressant-like activity of zinc in animal models. We now report that chronic treatment with zinc induced an increase in cortical but not hippocampal BDNF mRNA level (Northern blot). Tranylcypromine, a classic antidepressant, increased BDNF mRNA level in both examined brain regions. This is the first demonstration that zinc increases the BDNF gene expression, which is the effect shared by most of clinically effective antidepressants.