脑源性神经营养因子对大鼠内脏痛的作用

目的:探讨脑源性神经营养因子(BDNF)对雌、雄大鼠内脏痛的作用.方法:雌、雄大鼠以腹腔注射乙酸建立内脏痛模型.在注射乙酸之前60min,大鼠腹腔注射anti-BDNF抗体,然后观察注射乙酸后60min内的行为学变化,计算扭体次数;行为学观察完成后,大鼠立即处死,用免疫组织化学方法观察即早基因c-Fos编码产物c-Fo...     

Possible involvement of brain-derived neurotrophic factor in the antinociceptive effect of antidepressants in neuropathic pain

Neuropathic pain, a chronic pain state caused by injury to the nervous system, usually responds poorly to standard pain treatment. Antidepressants have been used to treat neuropathic pain, and animal and clinical studies have showed beneficial effects. However, the mechanisms underlying antidepressant antinociceptive effect in neuropathic pain are still unknown. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, can modulate synaptic plasticity and neurotransmitter release across multiple neurotransmitter systems. Recent animal and human studies have demonstrated that antidepressants can increase central as well as plasma BDNF levels. In addition: (1) BDNF is produced by a subset of primary sensory neurons that are located in the dorsal root ganglion; (2) BDNF levels change in animal models of neuropathic pain; (3) BDNF can indirectly depress sensory neuron transmission in the dorsal horn. From these findings, it is proposed that BDNF may play an important role in the antidepressant antinociceptive effect in neuropathic pain. The notion of BDNF mediating the therapeutic mechanisms of antidepressant in neuropathic pain may help to select the specific type and the optimal dose of antidepressants for the treatment of neuropathic pain. Exploration of this hypothesis could provide a new direction in the treatment of neuropathic pain, as well as other pain disorders.     

Expression of brain-derived neurotrophic factor in rat dorsal root ganglia, spinal cord and gracile nuclei in experimental models of neuropathic pain.

Chronic constriction injury of the sciatic nerve and lumbar L5 and L6 spinal nerve ligation provide animal models for pain syndromes accompanying peripheral nerve injury and disease. In the present study, we evaluated changes in brain-derived neurotrophic factor (BDNF) immunoreactivity in the rat L4 and L5 dorsal root ganglia (DRG) and areas where afferents from the DRG terminates (the L4/5 spinal cord and gracile nuclei) in these experimental models of neuropathic pain. Chronic constriction injury induced significant increase in the percentage of small, medium and large BDNF-immunoreactive neurons in the ipsilateral L4 and L5 DRG. Following spinal nerve ligation, the percentage of large BDNF-immunoreactive neurons increased significantly, and that of small BDNF-immunoreactive neurons decreased markedly in the ipsilateral L5 DRG, while that of BDNF-immunoreactive L4 DRG neurons of all sizes showed marked increase. Both chronic constriction injury and spinal nerve ligation induced significant increase in the number of BDNF-immunoreactive axonal fibers in the superficial and deeper laminae of the L4/5 dorsal horn and the gracile nuclei on the ipsilateral side.Considering that BDNF may modulate nociceptive sensory inputs and that injection of antiserum to BDNF significantly reduces the sympathetic sprouting in the DRG and allodynic response following sciatic nerve injury, our results also may suggest that endogenous BDNF plays an important role in the induction of neuropathic pain after chronic constriction injury and spinal nerve ligation. In addition, the increase of BDNF in L4 DRG may contribute to evoked pain which is known to be mediated by input from intact afferent from L4 DRG following L5 and L6 spinal nerve ligation.     

脑源性神经营养因子对血管新生的作用

脑源性神经营养因子（brain—derived neurotrophic factor,BDNF）是神经营养因子家族的一员,对中枢和外周神经系统多种类型神经元的生长、发育、分化和再生具有重要作用。研究显示人脐静脉内皮细胞（HUVEC）、人脑血管内皮细胞等多种内皮细胞以及新生血管平滑肌细胞均能产生BDNF,而且BDNF对血管内皮细胞的生长发育起着重要的支持作用。因此我们推测BDNF可能在一定程度上参与了机体新生血管的形成。为此,我们对BDNF的体内体外促血管新生作用进行了研究。     

Differential induction of brain-derived neurotrophic factor mRNA in rat inferior olive subregions following unilateral labyrinthectomy

The effects of 17beta-estradiol and the anti-estrogen, tamoxifen, on methamphetamine-induced neurotoxicity of the nigrostriatal dopaminergic system were examined in ovariectomized CD-1 mice. In Experiment 1, striatal dopamine concentrations from estrogen treated mice were significantly greater than that from non-estrogen treated mice following methamphetamine. Dopamine concentrations from estrogen+tamoxifen+methamphetamine treated mice were decreased compared to estrogen+methamphetamine treated mice and not significantly different from those of tamoxifen+methamphetamine treated mice or mice receiving methamphetamine alone. These results suggest that estrogen is functioning as a neuroprotectant of methamphetamine-induced nigrostriatal dopaminergic neurotoxicity and that this neuroprotective effect of estrogen is abolished in the presence of tamoxifen. In Experiment 2, estrogen administration after methamphetamine treatment did not produce any significant changes in dopamine concentrations compared with methamphetamine treatment alone. The data from Experiment 2 show that estrogen cannot reverse the methamphetamine-induced neurotoxicity upon the nigrostriatal dopaminergic system. Similar results were observed for the potassium-stimulated dopamine outputs from these treatment conditions as evaluated with in vitro superfusion, although a difference between the two measures for the estrogen+methamphetamine treated group was obtained in Experiment 1. These results have important implications for estrogen-tamoxifen interactions upon the nigrostriatal dopaminergic system and the gender differences which are observed in Parkinson's disease and animal models of nigrostriatal dopaminergic neurotoxicity as well as for the proposed use of tamoxifen in pre-menopausal women at risk for breast cancer.     

Venlafaxine inhibits apoptosis of hippocampal neurons by up-regulating brain-derived neurotrophic factor in a rat depression model

Objective: To study the effect of venlafaxine on the expression of brain-derived neurotrophic factor (BDNF) in rat hippocampal neurons, as well as its inhibitory effect on apoptosis of hippocampal neurons. Methods: Differences in behavioral ability between the depression model group and the Venlafaxine treatment group were observed using behavioral, sucrose-water and open field tests. The rat hippocampal tissue was sliced, stained and observed for BDNF distribution by immunohistochemistry. Apoptosis of hippocampal neurons was detected by TUNEL. BDNF expression in the hippocampal tissue was detected by Western blot. Injury and apoptosis of the hippocampal tissue were observed by electron microscopy. Results: Behavioral test showed that venlafaxine effectively improved the behavioral abilities of depressed rats. Immunohistochemistry showed that venlafaxine markedly increased the BDNF expression in the rat hippocampus. TUNEL showed that venlafaxine markedly inhibited apoptosis of hippocampal neurons, which was also confirmed by electron microscopic observation of the pathologic sections. Conclusion: Venlafaxine improved the expression of BDNF through working on PI3k/PKB/eNOS pathway and repressed the apoptosis of hippocampal neurons.     

The effect of site and type of nerve injury on the expression of brain-derived neurotrophic factor in the dorsal root ganglion and on neuropathic pain behavior

A number of rat neuropathy models have been developed to simulate human neuropathic pain conditions, such as spontaneous pain, hyperalgesia, and allodynia. In the present study, to determine the relative importance of injury site (proximal or distal to the primary afferent neurons) and injury type (motor or sensory), we examined pain-related behaviors and changes of brain-derived neurotrophic factor expression in the dorsal root ganglion in sham-operated rats, and in the L5 dorsal rhizotomy, L5 ventral rhizotomy, L5 dorsal rhizotomy+ventral rhizotomy, and L5 spinal nerve transection models. L5 ventral rhizotomy and spinal nerve transection produced not only mechanical and heat hypersensitivity, but also an increase in brain-derived neurotrophic factor mRNA/protein in the L5 dorsal root ganglion at 7 days after surgery. In contrast, rats in the L5 dorsal rhizotomy and dorsal rhizotomy+ventral rhizotomy groups did not show both pain behaviors at 7 days after surgery, despite brain-derived neurotrophic factor upregulation in medium- and large-size neurons in the L5 dorsal root ganglion. On the other hand, L5 spinal nerve transection, but not dorsal rhizotomy, dorsal rhizotomy+ventral rhizotomy or ventral rhizotomy, increased the expression of brain-derived neurotrophic factor in the L4 dorsal root ganglion at 7 days after surgery. Taken together, these findings suggest that the upregulation of brain-derived neurotrophic factor expression in the L4 and L5 dorsal root ganglion neurons may be, at least in part, involved in the pathophysiological mechanisms of neuropathic pain and that the selective nerve root injury models may be useful for studying the underlying mechanisms of chronic pain after nerve injury.     

Differential adaptive changes on serotonin and noradrenaline transporters in a rat model of peripheral neuropathic pain

Serotonin and noradrenaline reuptake inhibitors have shown to produce antinociceptive effects in several animal models of neuropathic pain. In the present work, we have analyzed the density of brain and spinal serotonin and noradrenaline transporters (5-HTT and NAT) in a rat model of neuropathic pain, the spinal nerve ligation (SNL). Quantitative autoradiography revealed a significant decrease in the density of 5-HTT ([(3)H]citalopram binding) at the level of the lumbar spinal cord following 2 weeks of neuropathic surgery (lamina V, -40%: 6.01±0.64 nCi/mg tissue in sham-animals vs 3.59±1.56 in SNL-animals; lamina X, -30%: 9.10±2.00 vs 6.40±1.93 and lamina IX, -22%: 12.01±2.41 vs 9.42±1.58). By contrast, NAT density ([(3)H]nisoxetine binding) was significantly increased (lamina I-II, +34%: 2.20±0.45 vs 2.96±0.65; lamina V, +57%: 1.34±0.28 vs 2.11±0.66; and lamina IX, +58%: 2.39±0.71 vs 3.78±1.10). At supraspinal structures, SNL induced adaptive changes only in the density of 5-HTT (septal nuclei, +33%: 10.18±2.03 vs 13.53±1.14; CA3 field of hippocampus, +18%: 6.94±1.01 vs 8.21±0.81; paraventricular thalamic nucleus, +21%: 15.18±1.88 vs 18.35±2.08; lateral hypothalamic area, +40%: 12.68±1.90 vs 17.8±2.55; ventromedial hypothalamic nuclei, +19%: 7.16±0.92 vs 8.55±0.40; and dorsal raphe nucleus, +15%: 35.22±3.88 vs 40.68±3.11). Thus, we demonstrate, in the SNL model of neuropathic pain, the existence of opposite changes in the spinal expression of 5-HTT (down-regulation) and NAT (up-regulation), and the presence of supraspinal adaptive changes (up-regulation) only on 5-HTT density. These findings may help understanding the pathogeny of neuropathic pain and the differential analgesic action of antidepressants targeting 5-HTT and/or NAT transporters.     

腺病毒介导脑源性神经营养因子与脑出血模型大鼠内源性神经干细胞的分化

BACKGROUND:Previous studies showed that neurotrophic factor has a variety of functions, which can effectively maintain the survival of neurons after injury. OBJECTIVE:To observe the effect of adenovirus-mediated brain-derived neurotrophic factor on the differentiation of endogenous neural stem cells after intracerebral hemorrhage in rats. METHODS:A total of 90 Sprague-Dawley rat models of cerebral hemorrhage were made. At 12 hours after cerebral hemorrhage, 5-bromodeoxyuridine (BrdU) was intraperitoneally injected, twice a day, for 10 consecutive days. After model establishment, rats were randomly divided into three groups, 30 rats in each group, and were respectively subjected to brain stereotaxic injection of adenovirus vector, adenovirus-mediated brain-derived neurotrophic factor and physiological saline. At 1 day, 3 days, 1 week, 2 weeks, 3 weeks, and 4 weeks, neurological deficit score was evaluated. Absorbance value of growth associated protein around the area of hematoma after intracerebral hemorrhage was measured. At 4 weeks after injection, double immunostaining was used to detect the expression of BrdU/NeuN and BrdU/glial fibrillary acidic protein (GFAP).  RESULTS AND CONCLUSION:(1) With the passage of time, nerve function defect score decreased in the three groups. At 1-4 weeks after injection, nerve function deficit scores were lower in the adenovirus-mediated brain-derived neurotrophic factor group than that in the adenovirus vector group and saline group (P < 0.05). (2) With the passage of time, the average absorbance of three groups in the peri-hematoma region first increased and then decreased. The absorbance value was higher in the adenovirus-mediated brain-derived neurotrophic factor group than in the adenovirus vector group and saline group at 3 days-4 weeks (P < 0.05). (3) BrdU/NeuN and BrdU/GFAP rates were significantly higher in the adenovirus-mediated brain-derived neurotrophic factor group than that of adenovirus vector group and saline group (P < 0.05). (4) The results show that the brain-derived neurotrophic factor mediated by adenovirus, and intervention on cerebral hemorrhage in rats can effectively promote the differentiation of endogenous neural stem cells, and promote the recovery of neural function in animal.     

Differential activation of dendritic cells by nerve growth factor and brain-derived neurotrophic factor

BACKGROUND: Neurotrophins are involved in inflammatory reactions influencing several cells in health and disease including allergy and asthma. Dendritic cells (DCs) play a major role in the induction of inflammatory processes with an increasing role in allergic diseases as well. OBJECTIVE: The aim of this study was to investigate the influence of neurotrophins on DC function. METHODS: Monocyte-derived dendritic cells were generated from allergic and non-allergic donors. Neurotrophin receptors were demonstrated by western blotting, flow cytometry and fluorescence microscopy. Activation of small GTPases was evaluated by pull-down assays. DCs were incubated with nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and supernatants were collected for measurement of IL-4, IL-6, IL-10, IL-12p70, TNF-alpha and TGF-beta. RESULTS: Receptor proteins were detectable by western blot, fluorescence activated cell sorting analysis and fluorescence microscopy. Signalling after neurotrophin stimulation occurred in a ligand-specific pattern. NGF led to decreased RhoA and increased Rac activation, while BDNF affected RhoA and Rac activity in a reciprocal fashion. Cells of allergics released a significantly increased amount of IL-6, while for healthy subjects a significantly higher amount of IL-10 was found. CONCLUSION: These data indicate that DCs are activated by the neurotrophins NGF and BDNF by different pathways in a receptor-dependant manner. These cells then may initiate inflammatory responses based on allergic sensitization releasing preferred cytokines inducing tolerance or a T-helper type 2 response.     

Differential effects of spinally applied glycine transporter inhibitors on nociception in a rat model of neuropathic pain

Changes in glycinergic neurotransmission in the spinal cord dorsal horn are critically involved in the development of pathological pain. Since the concentration of glycine in the synaptic cleft is controlled by specialized proteins, the glycine transporters GlyT1 and GlyT2, manipulation of this system might have significant effects on nociception. In the present study, we investigated the effects of the spinally applied glycine transporter inhibitors ALX 5407 (GlyT1) and ALX 1393 (GlyT2) on nociceptive behavior in the chronic constriction injury model of neuropathic pain in male Wistar rats. After implementation of neuropathy, the animals were injected with three dosages of ALX 5407 and ALX 1393 (10, 50 and 100 microg) via an intrathecal catheter (n = 8 each). Subsequently, nociceptive behavior was evaluated regarding thermal hyperalgesia (Hargreaves method) and mechanical sensitization (von Frey filaments) over 240 min after application. Inhibition of GlyT1 by ALX 5407 had differential dose-dependent effects. While the highest and the lowest concentrations were antinociceptive, the medium dose evoked pronociceptive effects. The GlyT2 inhibitor ALX 1393 was only effective in the highest concentration at which it exerted significant antinociception. However, in the same dose, ALX 1393 caused remarkable side effects such as respiratory depression and motor deficits in three animals. Our findings indicate that inhibition of glycine transporters is capable of evoking significant effects on nociceptive behavior in neuropathic pain. Whether glycine transporter inhibitors have the capability to gain clinical relevance as analgesic compounds on the long run has to be elucidated in further investigations.     

Ultrastructural localization of brain-derived neurotrophic factor in rat primary sensory neurons

In a previous study we have shown that brain-derived neurotrophic factor (BDNF) is present in a subpopulation of small- to medium-sized sensory neurons in the dorsal root ganglia (DRG) and is anterogradely transported in both the peripheral and central processes. Within the spinal cord, BDNF is localized to varicosities of sensory nerve terminals in laminae I and II of the dorsal horn. This study raised the question of whether BDNF is localized in synaptic vesicles of the afferent nerve terminals. Using immunohistochemical and immunocytochemical techniques we have now investigated the ultrastructural localization of BDNF in the spinal cord of the rat. In addition, its colocalization with the low affinity neurotrophin receptor, p75, and calcitonin gene related peptide (CGRP) was also investigated. In lamina II of the spinal cord, BDNF immunoreactivity was restricted to nerve terminals. The reaction product appeared associated with dense-cored and clear vesicles of terminals superficial laminae. Double labelling experiments at the light microscopic level showed that 55% of BDNF immunoreactive neurons in DRG are colocalized with CGRP and many nerve terminals in laminae I and II of the spinal cord contained both BDNF and CGRP immunoreactivities. The results of double labelling at the ultrastructural level showed that most BDNF-ir (immunoreactive) nerve terminals contained CGRP or the low affinity neurotrophin receptor, p75, but not vice versa. These results point to the conclusion that BDNF may be released in parallel with neurotransmitters from nerve terminals in the spinal cord from a subpopulation of nociceptive primary afferents.     

Differential regulation of brain-derived neurotrophic factor messenger RNA cellular expression in the adult rat visual cortex.

In this study, we report a comparative analysis of the distribution of brain-derived neurotrophic factor messenger RNA in the binocular primary visual cortex of rats analysed at the end of the critical period for monocular deprivation (postnatal day 35) and during adulthood (postnatal day 90). High-resolution non-isotopic in situ hybridization coupled with Nissl staining allowed to determine the relative number of neurons expressing brain-derived neurotrophic factor messenger RNA. In postnatal day 90 rats, the relative number of neurons positive for brain-derived neurotrophic factor messenger RNA significantly decreases in layer II/III with respect to postnatal day 35 animals, being constant in all the other cortical layers. Moreover, we demonstrate that dark rearing for 22 days, starting from postnatal day 90, determines: (i) a decrease of the overall level of brain-derived neurotrophic factor messenger RNA with a consequent reduction of labelling intensity in all cells throughout cortical layers II-VI; (ii) an increase of cell numbers expressing brain-derived neurotrophic factor messenger RNA in layers IV and V; and (iii) a decreased intensity of staining for brain-derived neurotrophic factor messenger RNA in dendrites after dark rearing. A re-exposure to light for 2 h after the period of darkness almost restores the number of brain-derived neurotrophic factor RNA-positive neurons. We conclude that the maturation of brain-derived neurotrophic factor messenger RNA in neurons of layer II/III goes beyond postnatal days 35-40, which can be considered the end of the critical period [Fagiolini M. et al. (1994) Vis. Res., 34, 709-720]. Moreover, we show that the cellular expression of brain-derived neurotrophic factor messenger RNA is regulated by light in adult rats as well as during development.     

Electroacupuncture potentiates the antiallodynic effect of intrathecal neostigmine in a rat model of neuropathic pain

This study was performed to examine whether electroacupuncture potentiates the neostigmine-induced antiallodynia in neuropathic pain rats. Although intrathecal neostigmine (0.05, 0.1, and 0.3 microg) dose-dependently relieved cold allodynia, 0.3 microg neostigmine caused side effects. The coapplication of 0.1 microg neostigmine and electroacupuncture, however, produced potent antiallodynia, which was parallel to the effect of 0.3 microg neostigmine, without side effects. These results indicate that electroacupuncture can enhance the antiallodynic action of intrathecal neostigmine.     

Actions of brain-derived neurotrophic factor on spinal nociceptive transmission during inflammation in the rat

The aim of the current study was to investigate whether, and if so how, brain-derived neurotrophic factor (BDNF) acts to develop the spinal sensitization underlying inflammation-induced hyperalgesia. In spinal cord slice preparations from rats with inflammation induced by complete Freund's adjuvant (CFA), BDNF, but not nerve growth factor (NGF) or neurotrophin-3 (NT-3), acted presynaptically to increase the frequency of excitatory miniature EPSCs in substantia gelatinosa (SG) neurones of the CFA-treated, but not untreated rats, through activation of lidocaine (lignocaine)-sensitive, TTX-resistant Na⁺ channels. This effect was observed in the spinal cord slices of the CFA-treated rat only 2–4 days after the CFA injection. On the other hand, the number of monosynaptic Aβ afferent inputs to the SG significantly increased 1 week after the onset of the inflammation, and this increase was significantly suppressed by treatment with anti-BDNF antiserum administered 1 day before and just after the CFA injection. In addition, the treatment with anti-BDNF antiserum significantly attenuated the CFA-induced hyperalgesia and/or allodynia. These findings, taken together, suggest that BDNF, which is considered to be released from the sensitized primary afferents, increases the excitability of SG neurones through its action on the presynaptic terminals. BDNF may thereafter induce monosynaptic Aβ afferents to the SG, thereby developing hyperalgesia and/or allodynia during inflammation.     

Monocular deprivation decreases brain-derived neurotrophic factor immunoreactivity in the rat visual cortex

Neurotrophins play a crucial role in the development and activity-dependent plasticity of the visual cortex [Berardi N. et al. (1994) Proc. natn. Acad. Sci. U.S.A. 91, 684-688; Bonhoeffer T. (1996) Curr. Opin. Neurobiol. 6, 119-126; Cellerino A. and Maffei L. (1996) Prog. Neurobiol. 49, 53-71; Domenici L. et al. (1994) NeuroReport 5, 2041-2044; Galuske R. A. W. et al (1996) Eur. J. Neurosci. 8, 1554-1559; Katz L. C. and Shatz C. J. (1996) Science 274, 1133-1138; Maffei L. et al. (1992) J. Neurosci. 12, 4651-4662; Pizzorusso T. and Maffei L. (1996) Curr. Opin. Neurol. 9, 122-125; Thoenen H. (1995) Science 270, 593-598]. As a possible mechanism of action, it has been postulated that the activity-dependent expression of neurotrophins by cortical cells could regulate synapse stabilization during the first period of postnatal life (critical period). Indeed, brain-derived neurotrophic factor messenger RNA expression in the visual cortex is regulated by neuronal activity as well as during development [Castrén E. et al. (1992) Proc. natn. Acad. Sci. U.S.A. 89, 9444-9448]. Moreover, we showed that monocular deprivation decreases brain-derived neurotrophic factor messenger RNA levels in the visual cortex receiving input from the deprived eye [Bozzi Y. et al. (1995) Neuroscience 69, 1133-1144]. What is missing, however, is the demonstration that brain-derived neurotrophic factor protein expression follows that of brain-derived neurotrophic factor messenger RNA. The aim of the present study is to fill this important gap in order to support the hypothesis that brain-derived neurotrophic factor is fundamental in the plasticity of the visual cortex. We found that brain-derived neurotrophic factor immunoreactivity peaks during the critical period and that it is preferentially localized in layers II-III and V-VI. We also demonstrated that monocular deprivation determines a decrease of brain-derived neurotrophic factor immunoreactivity exclusively in the visual cortex contralateral to the deprived eye. Our results support the proposed role for brain-derived neurotrophic factor in the development and activity-dependent plasticity of the visual cortex [Cabelli R. J. et al. (1995) Science 267, 1662-1666].     

Hippocampal neurokinin-1 receptor and brain-derived neurotrophic factor gene expression is decreased in rat models of pain and stress

Acute or chronic stress can alter hippocampal structure, cause neuronal damage, and decrease hippocampal levels of the neurotrophin brain-derived neurotrophic factor (BDNF). The tachykinin substance P and its neurokinin-1 (NK-1) receptor may play a critical role in neuronal systems that process nociceptive stimuli; their importance in stress-activated systems has recently been demonstrated by the antidepressant-like actions of NK-1 receptor antagonists. However, the functional similarities between neurokinin receptors in the hippocampus and those in sensory systems are poorly understood, as is the significance of hippocampal NK-1 receptor in the context of chronic pain. Therefore, we investigated the effects of immobilization stress or inflammatory stimuli on NK-1 receptor and BDNF gene expression in the rat hippocampus. Rats received an acute or chronic immobilization stress, or an acute (formalin) or chronic (complete Freund's adjuvant) inflammatory stimulus to the right hind paw. Subsequently hippocampal volume and specific gravity were measured and NK-1 receptor and BDNF mRNA levels quantified using ribonuclease protection assays. Results showed that either stress or pain down-regulates expression of both NK-1 receptor and BDNF genes in the hippocampus. Hippocampal volume was increased by either pain or stress; this may be due to edema (decreased specific gravity). Thus, BDNF and NK-1 receptor gene plasticity may reflect sensory activation or responses to neuronal injury. These data may provide useful markers of hippocampal activation during chronic pain, and suggest similarities in the mechanisms underlying chronic pain and depression.     

Exercise primes a molecular memory for brain-derived neurotrophic factor protein induction in the rat hippocampus

Exercise is an important facet of behavior that enhances brain health and function. Increased expression of the plasticity molecule brain-derived neurotrophic factor (BDNF) as a response to exercise may be a central factor in exercise-derived benefits to brain function. In rodents, daily wheel-running exercise increases BDNF gene and protein levels in the hippocampus. However, in humans, exercise patterns are generally less rigorous, and rarely follow a daily consistency. The benefit to the brain of intermittent exercise is unknown, and the duration that exercise benefits endure after exercise has ended is unexplored. In this study, BDNF protein expression was used as an index of the hippocampal response to exercise. Both daily exercise and alternating days of exercise increased BDNF protein, and levels progressively increased with longer running duration, even after 3 months of daily exercise. Exercise on alternating days was as effective as daily exercise, even though exercise took place only on half as many days as in the daily regimen. In addition, BDNF protein remained elevated for several days after exercise ceased. Further, after prior exercise experience, a brief second exercise re-exposure insufficient to cause a BDNF change in naïve animals, rapidly reinduced BDNF protein to levels normally requiring several weeks of exercise for induction. The protein reinduction occurred with an intervening “rest” period as long as 2 weeks. The rapid reinduction of BDNF by an exercise stimulation protocol that is normally subthreshold in naïve animals suggests that exercise primes a molecular memory for BDNF induction. These findings are clinically important because they provide guidelines for optimizing the design of exercise and rehabilitation programs, in order to promote hippocampal function.     

Role of brain-derived neurotrophic factor in Huntington's disease

Neurotrophic factors are essential contributors to the survival of peripheral and central nervous system (CNS) neurons, and demonstration of their reduced availability in diseased brains indicates that they play a role in various neurological disorders. This paper will concentrate on the role of brain-derived neurotrophic factor (BDNF) in the survival and activity of the neurons that die in Huntington's disease (HD) by reviewing the evidence indicating that it involves profound changes in BDNF levels and that attempts to restore these levels are therapeutically interesting.

BDNF is a small dimeric protein that is widely expressed in adult mammalian brain and has been shown to promote the survival of all major neuronal types affected in Alzheimer's disease (AD) and Parkinson's disease (PD). Furthermore, cortical BDNF production is required for the correct activity of the corticostriatal synapse and the survival of the GABA-ergic medium-sized spiny striatal neurons that die in HD. We will highlight the available data concerning changes in BDNF levels in HD cells, mice and human postmortem samples, describe the molecular evidence underlying this alteration, and review the data concerning the impact of the experimental manipulation of BDNF levels on HD progression. Such studies have revealed a major loss of BDNF protein in the striatum of HD patients which may contribute to the clinical manifestations of the disease. They have also opened up a molecular window into the underlying pathogenic mechanism and new therapeutic perspectives by raising the possibility that one of the mechanisms triggering the reduction in BDNF in HD may also affect the activity of many other neuronal proteins.     

Differential patterns of nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 mRNA and protein levels in developing regions of rat brain

The present studies were undertaken to characterize the regional and temporal patterns of neurotrophin messenger RNA and protein levels for beta-nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 in the developing CNS. We have examined the levels of these neurotrophin messenger RNAs with ribonuclease protection assays and corresponding protein levels with enzyme-linked immunosorbent assays in the developing Long-Evans rat hippocampus, neocortex and cerebellum on postnatal days 1, 7, 14, 21, and 92. In addition, immunohistochemistry was used to localize the neurotrophins in these developing brain regions. Results indicated that in neocortex and hippocampus, messenger RNA for both nerve growth factor and brain-derived neurotrophic factor increased in an age-dependent manner, reaching a plateau by postnatal day 14. In the neocortex, nerve growth factor and brain-derived neurotrophic factor protein levels both peaked at postnatal day 14. In hippocampus, nerve growth factor protein peaked at postnatal day 7 while brain-derived neurotrophic factor peaked at postnatal day 14. In cerebellum, nerve growth factor messenger RNA levels were flat, while nerve growth factor protein peaked at postnatal day 7. Brain-derived neurotrophic factor messenger RNA increased in an age-dependent manner while the pattern for its protein levels was mixed. Neurotrophin-3 messeger RNA levels increased in an age-dependent manner in hippocampus, peaked at postnatal day14 in cerebellum, and no changes occurred in neocortex. Neurotrophin-3 protein was at its peak at postnatal day 1 and thereafter decreased at other postnatal days in all three brain regions. Results of neurotrophin immunohistochemistry often paralleled and complemented enzyme-linked immunosorbent assay data, demonstrating specific cell groups containing neurotrophin proteins in these regions. Within each region, patterns with regard to messenger RNA and respective protein levels for each neurotrophin were unique. No consistent relationship between patterns of neurotrophin messenger RNAs and their cognate proteins was observed between regions. The different regional patterns for neurotrophin messengerRNA and protein levels in each brain region indicate that messenger RNA studies of neurotrophin messenger RNA must be augmented by protein determination to fully characterize spatial and temporal neurotrophin distribution.