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Cerebrolysin Ameloriates Cognitive Deficits in Type III Diabetic Rats  [PDF]
Gehan S. Georgy, Noha N. Nassar, Hanaa A. Mansour, Dalaal M. Abdallah
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0064847
Abstract: Cerebrolysin (CBL), a mixture of several active peptide fragments and neurotrophic factors including brain-derived neurotrophic factor (BDNF), is currently used in the management of cognitive alterations in patients with dementia. Since Cognitive decline as well as increased dementia are strongly associated with diabetes and previous studies addressed the protective effect of BDNF in metabolic syndrome and type 2 diabetes; hence this work aimed to evaluate the potential neuroprotective effect of CBL in modulating the complications of hyperglycaemia experimentally induced by streptozotocin (STZ) on the rat brain hippocampus. To this end, male adult Sprague Dawley rats were divided into (i) vehicle- (ii) CBL- and (iii) STZ diabetic-control as well as (iv) STZ+CBL groups. Diabetes was confirmed by hyperglycemia and elevated glycated haemoglobin (HbA1c%), which were associated by weight loss, elevated tumor necrosis factor (TNF)-α and decreased insulin growth factor (IGF)-1β in the serum. Uncontrolled hyperglycemia caused learning and memory impairments that corroborated degenerative changes, neuronal loss and expression of caspase (Casp)-3 in the hippocampal area of STZ-diabetic rats. Behavioral deficits were associated by decreased hippocampal glutamate (GLU), glycine, serotonin (5-HT) and dopamine. Moreover, diabetic rats showed an increase in hippocampal nitric oxide and thiobarbituric acid reactive substances versus decreased non-protein sulfhydryls. Though CBL did not affect STZ-induced hyperglycemia, it partly improved body weight as well as HbA1c%. Such effects were associated by enhancement in both learning and memory as well as apparent normal cellularity in CA1and CA3 areas and reduced Casp-3 expression. CBL improved serum TNF-α and IGF-1β, GLU and 5-HT as well as hampering oxidative biomarkers. In conclusion, CBL possesses neuroprotection against diabetes-associated cerebral neurodegeneration and cognitive decline via anti-inflammatory, antioxidant and antiapototic effects.
An Overview of Brain-Derived Neurotrophic Factor and Implications for Excitotoxic Vulnerability in the Hippocampus  [PDF]
Patrick S. Murray,Philip V. Holmes
International Journal of Peptides , 2011, DOI: 10.1155/2011/654085
Abstract: The present paper examines the nature and function of brain-derived neurotrophic factor (BDNF) in the hippocampal formation and the consequences of changes in its expression. The paper focuses on literature describing the role of BDNF in hippocampal development and neuroplasticity. BDNF expression is highly sensitive to developmental and environmental factors, and increased BDNF signaling enhances neurogenesis, neurite sprouting, electrophysiological activity, and other processes reflective of a general enhancement of hippocampal function. Such increases in activity may mediate beneficial effects such as enhanced learning and memory. However, the increased activity also comes at a cost: BDNF plasticity renders the hippocampus more vulnerable to hyperexcitability and/or excitotoxic damage. Exercise dramatically increases hippocampal BDNF levels and produces behavioral effects consistent with this phenomenon. In analyzing the literature regarding exercise-induced regulation of BDNF, this paper provides a theoretical model for how the potentially deleterious consequences of BDNF plasticity may be modulated by other endogenous factors. The peptide galanin may play such a role by regulating hippocampal excitability. 1. Brain-Derived Neurotrophic Factor Overview Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family, a group of structurally related polypeptide growth factors. The family also includes nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4/5) [1]. Other neurotrophins have also been identified, NT-6 and NT-7; however, these likely do not exist in mammals [2–4]. Neurotrophins activate one or more of the high-affinity tropomyosin-receptor kinase (Trk) receptor family [1, 5, 6], as well as the low-affinity p75 neurotrophin receptor (p75NTR) [7]. Neurotrophins direct growth and differentiation in the developing nervous system [1, 3, 6, 8]. Levels of the different neurotrophins relate in a predictable pattern to stages of embryonic development. Infusion of BDNF into the adult brain promotes neurogenesis [9, 10], and dendritic spine reorganization in the rat hippocampal formation [11]. BDNF gene transfection triggers dendritic and axonal branching in dentate gyrus (DG) granule cell cultures [12] while mice with a targeted gene deletion show substantial impairment in normal cerebellar development, among other developmental and behavioral deficits [13]. Trk receptors precipitate the activation of many signaling cascades, including phospholipase C (PLC), phosphoinositide 3-kinase (PI3K), and Ras [14, 15],
Brain-derived neurotrophic factor in VMH as the causal factor for and therapeutic tool to treat visceral adiposity and hyperleptinemia in type 2 diabetic Goto–Kakizaki rats  [PDF]
Fumihiko Maekawa
Frontiers in Synaptic Neuroscience , 2013, DOI: 10.3389/fnsyn.2013.00007
Abstract: We previously reported that the type 2 diabetic Goto–Kakizaki (GK) rats at young adult ages (6–12 weeks) exhibited increased visceral fat mass and hyperleptinemia, due to hyperphagia caused primarily by neuropeptide Y (NPY) overexpression in the hypothalamic arcuate nucleus. Later, we found that GK rats continued to exhibit mesenteric fat accumulation and hyperleptinemia at least until 26 weeks of age, while hyperphagia and NPY overexpression ceased at 15 weeks of age. Therefore, we hypothesized that the long-lasting fat accumulation and hyperleptinemia are due to unidentified brain dysfunction other than NPY overexpression. In GK rats aged 26 weeks, glucose transporter-2 (GLUT2) mRNA expression in ventromedial hypothalamus (VMH) was markedly reduced in parallel with significant decreases in brain-derived neurotrophic factor (BDNF) mRNA level and BDNF-expressing cell numbers in the VMH. Pharmacologic inhibition of glucose utilization reduced BDNF mRNA expression in VMH in vivo and in vitro. The results suggested that impaired glucose utilization caused the reduction of BDNF. On the other hand, intracerebroventricular injection of BDNF for 6 days ameliorated hyperleptinemia in a long-lasting manner concurrently with feeding suppression in GK rats. Restricted feeding paired to BDNF-treated rats reduced plasma leptin level only transiently. BDNF treatment also reduced mesenteric fat mass in GK rats. These results reveal a novel action mode of BDNF to long-lastingly counteract visceral adiposity and hyperleptinemia in addition to and independently of its anorexigenic action. These results suggest that visceral fat accumulation and hyperleptinemia are at least partly due to the reduction of BDNF in VMH primarily caused by impaired glucose utilization in GK rats. The BDNF supplementation could provide an effective treatment of visceral obesity, hyperleptinemia and leptin resistance in type 2 diabetes.
Stress Leads to Contrasting Effects on the Levels of Brain Derived Neurotrophic Factor in the Hippocampus and Amygdala  [PDF]
Harini Lakshminarasimhan,Sumantra Chattarji
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0030481
Abstract: Recent findings on stress induced structural plasticity in rodents have identified important differences between the hippocampus and amygdala. The same chronic immobilization stress (CIS, 2h/day) causes growth of dendrites and spines in the basolateral amygdala (BLA), but dendritic atrophy in hippocampal area CA3. CIS induced morphological changes also differ in their temporal longevity- BLA hypertrophy, unlike CA3 atrophy, persists even after 21 days of stress-free recovery. Furthermore, a single session of acute immobilization stress (AIS, 2h) leads to a significant increase in spine density 10 days, but not 1 day, later in the BLA. However, little is known about the molecular correlates of the differential effects of chronic and acute stress. Because BDNF is known to be a key regulator of dendritic architecture and spines, we investigated if the levels of BDNF expression reflect the divergent effects of stress on the hippocampus and amygdala. CIS reduces BDNF in area CA3, while it increases it in the BLA of male Wistar rats. CIS-induced increase in BDNF expression lasts for at least 21 days after the end of CIS in the BLA. But CIS-induced decrease in area CA3 BDNF levels, reverses to normal levels within the same period. Finally, BDNF is up regulated in the BLA 1 day after AIS and this increase persists even 10 days later. In contrast, AIS fails to elicit any significant change in area CA3 at either time points. Together, these findings demonstrate that both acute and chronic stress trigger opposite effects on BDNF levels in the BLA versus area CA3, and these divergent changes also follow distinct temporal profiles. These results point to a role for BDNF in stress-induced structural plasticity across both hippocampus and amygdala, two brain areas that have also been implicated in the cognitive and affective symptoms of stress-related psychiatric disorders.
Alterations in Brain-Derived Neurotrophic Factor in the Mouse Hippocampus Following Acute but Not Repeated Benzodiazepine Treatment  [PDF]
Stephanie C. Licata, Nina M. Shinday, Megan N. Huizenga, Shayna B. Darnell, Gavin R. Sangrey, Uwe Rudolph, James K. Rowlett, Ghazaleh Sadri-Vakili
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0084806
Abstract: Benzodiazepines (BZs) are safe drugs for treating anxiety, sleep, and seizure disorders, but their use also results in unwanted effects including memory impairment, abuse, and dependence. The present study aimed to reveal the molecular mechanisms that may contribute to the effects of BZs in the hippocampus (HIP), an area involved in drug-related plasticity, by investigating the regulation of immediate early genes following BZ administration. Previous studies have demonstrated that both brain derived neurotrophic factor (BDNF) and c-Fos contribute to memory- and abuse-related processes that occur within the HIP, and their expression is altered in response to BZ exposure. In the current study, mice received acute or repeated administration of BZs and HIP tissue was analyzed for alterations in BDNF and c-Fos expression. Although no significant changes in BDNF or c-Fos were observed in response to twice-daily intraperitoneal (i.p.) injections of diazepam (10 mg/kg + 5 mg/kg) or zolpidem (ZP; 2.5 mg/kg + 2.5 mg/kg), acute i.p. administration of both triazolam (0.03 mg/kg) and ZP (1.0 mg/kg) decreased BDNF protein levels within the HIP relative to vehicle, without any effect on c-Fos. ZP specifically reduced exon IV-containing BDNF transcripts with a concomitant increase in the association of methyl-CpG binding protein 2 (MeCP2) with BDNF promoter IV, suggesting that MeCP2 activity at this promoter may represent a ZP-specific mechanism for reducing BDNF expression. ZP also increased the association of phosphorylated cAMP response element binding protein (pCREB) with BDNF promoter I. Future work should examine the interaction between ZP and DNA as the cause for altered gene expression in the HIP, given that BZs can enter the nucleus and intercalate into DNA directly.
Conditional downregulation of brain- derived neurotrophic factor and tyrosine kinase receptor B blocks epileptogenesis in the human temporal lobe epilepsy hippocampus  [cached]
Hou Xiaohua,Wang Xiaoran,Zhang Liming
Neurology India , 2010,
Abstract: Backgroud : Brain-derived neurotrophic factor (BDNF) has been implicated as a potential therapeutic target in temporal lobe epilepsy (TLE). However, whether BDNF exerts an epileptogenic or antiepileptogenic function remains controversial. Materials and Methods : BDNF/tyrosine kinase receptor B (trkB) expression levels were comparatively assessed in the hippocampal tissue of TLE patients with (HS group) and without hippocampal sclerosis (non-HS group) as well as from non-epileptic controls. Results : Immunohistochemistry and immunoblot analysis revealed a marked increase in BDNF/trkB expression in the dentate gyrus and CA3 regions of HS and non-HS groups. The lack of any differences in expression levels was observed between HS and non-HS patients. Meanwhile, treatment with VPA (Valproic acid, anti-epileptic drug) resulted in a significant down-regulation of BDNF/trkB protein expression in sclerotic and non-sclerotic hippocampus (P < 0.001). In contrast, no marked change was noticed in VPA-untreated and OA-treated groups (sodium octanoate). Conclusion : These results suggest that the up-regulation of BDNF/trkB pathway might be at least in part responsible for the epileptogenesis.
Brain-derived Neurotrophic Factor Regulates Energy Expenditure Through the Central Nervous System in Obese Diabetic Mice  [PDF]
Takeshi Nonomura,Atsushi Tsuchida,Michiko Ono-Kishino,Tsutomu Nakagawa,Mutsuo Taiji,Hiroshi Noguchia
Experimental Diabetes Research , 2001, DOI: 10.1155/edr.2001.201
Abstract: It has been previously demonstrated that brain-derived neurotrophic factor (BDNF) regulates glucose metabolism and energy expenditure in rodent diabetic models such as C57BL/KsJ-leprdb/leprdb (db/db) mice. Central administration of BDNF has been found to reduce blood glucose in db/db mice, suggesting that BDNF acts through the central nervous system. In the present study we have expanded these investigations to explore the effect of central administration of BDNF on energy metabolism. Intracerebroventricular administration of BDNF lowered blood glucose and increased pancreatic insulin content of db/db mice compared with vehicle-treated pellet pair-fed db/db mice. While body temperatures of the pellet pair-fed db/db mice given vehicle were reduced because of restricted food supply in this pair-feeding condition, BDNF treatment remarkably alleviated the reduction of body temperature suggesting the enhancement of thermogenesis. BDNF enhanced norepinephrine turnover and increased uncoupling protein-1 mRNA expression in the interscapular brown adipose tissue. Our evidence indicates that BDNF activates the sympathetic nervous system via the central nervous system and regulates energy expenditure in obese diabetic animals.
Neurokinin-1 (NK-1) receptor and brain-derived neurotrophic factor (BDNF) gene expression is differentially modulated in the rat spinal dorsal horn and hippocampus during inflammatory pain
Vanja Duric, Kenneth E McCarson
Molecular Pain , 2007, DOI: 10.1186/1744-8069-3-32
Abstract: To date, pain-induced peripheral and central sensory activation has been well characterized; however, little emphasis has been placed on studying the physiological mechanisms of the stress-like component of pain and its relationship to mood or affect. The importance of the emotional aspects of chronic pain and their impact on cognition and the overall perception of the nociceptive stimuli is augmented by clinical observations that majority of chronic pain patients often suffer from various forms of depressive illnesses [1-4]. The hippocampus, one of the main regulators of affect within the limbic system, has been previously shown to exhibit a robust stress-induced neurodegenerative plasticity related to the pathophysiology of depression [5-8]. Furthermore, the hippocampus has also been associated with the processing of pain-related information, particularly its potential role in shaping the affective-motivational response to noxious sensory stimulation. For example, peripheral administration of formalin was shown to attenuate levels of Fos protein in the rat hippocampus [9], while microinjections of lidocaine or glutamate receptor antagonists directly into the dorsal hippocampal formation decreased formalin-related nociceptive behaviors [10,11].The tachykinin neuropeptide substance P (SP) and brain-derived neurotrophic factor (BDNF), each expressed by a subset of primary sensory neurons, are known modulators of nociceptive processing within the CNS [12-14]. Upon tissue injury or noxious stimulation, SP and BDNF are released into laminae I and II of the spinal cord dorsal horn, where through activation of their respective postsynaptic receptors, neurokinin-1 (NK-1) and tyrosine kinase B (trkB), contribute to development of hyperalgesia and central sensitization associated with chronic pain [15-18]. Both NK-1 receptors and BDNF are also highly expressed in the limbic system, primarily the amygdala, the hippocampus and the hypothalamus [14,19,20]. Their potential invol
Vagal Nerve Stimulation Rapidly Activates Brain-Derived Neurotrophic Factor Receptor TrkB in Rat Brain  [PDF]
Havan Furmaga, Flavia Regina Carreno, Alan Frazer
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0034844
Abstract: Background Vagal nerve stimulation (VNS) has been approved for treatment-resistant depression. Many antidepressants increase expression of brain-derived neurotrophic factor (BDNF) in brain or activate, via phosphorylation, its receptor, TrkB. There have been no studies yet of whether VNS would also cause phosphorylation of TrkB. Methods Western blot analysis was used to evaluate the phosphorylation status of TrkB in the hippocampus of rats administered VNS either acutely or chronically. Acute effects of VNS were compared with those caused by fluoxetine or desipramine (DMI) whereas its chronic effects were compared with those of sertraline or DMI. Results All treatments, given either acutely or chronically, significantly elevated phosphorylation of tyrosines 705 and 816 on TrkB in the hippocampus. However, only VNS increased the phosphorylation of tyrosine 515, with both acute and chronic administration causing this effect. Pretreatment with K252a, a nonspecific tyrosine kinase inhibitor, blocked the phosphorylation caused by acute VNS at all three tyrosines. Downstream effectors of Y515, namely Akt and ERK, were also phosphorylated after acute treatment with VNS, whereas DMI did not cause this effect. Conclusion VNS rapidly activates TrkB phosphorylation and this effect persists over time. VNS-induced phosphorylation of tyrosine 515 is distinct from the effect of standard antidepressant drugs.
V. Rahimi-Movaghar,H. Q. Yan,Y. Li,X. Ma
Acta Medica Iranica , 2005,
Abstract: Glial cell line-derived neurotrophic factor (GDNF) plays important roles not only for the differentiation of neurons during normal development but also for the survival and recovery of many populations of mature neurons. The effect of traumatic brain injury (TBI) on the expression of GDNF is currently unknown. To determine if there is alteration in GDNF after TBI we examined the effect of controlled cortical impact (CCI) injury on GDNF protein levels at 6 hours, 1 day, 1 week, and 4 weeks following injury by utilizing a commercially available antibody specific to GDNF. Rats were anesthetized and surgically prepared for CCI injury (4 m/sec, 2.7 mm) and sham surgery. Injured and sham animals (n=6 per group) were sacrificed at 6 hours, 1 day, 1 week, and 4 weeks and perfused with 4% paraformaldehyde. Coronal sections (35 mm thick) were cut through the hippocampus. An increased expression of GDNF protein was observed by immunohistochemistry in the dentate gyrus of hippocampus and the cortex in injured rats compared to sham controls. The increased expression of GDNF was more evidently observed in the ipsilateral dentate gyrus and the area around the contusion in the cortex. In the cortex, GDNF immunoreactivity appeared greatest in cells with glial morphology but in the hippocampus, GDNF immunoreactivity was greatest in neuronal-like cells. These changes were observed at 1 day, 1 and 4 weeks postinjury. We speculate that the up-regulation of the GDNF protein may reflect its neurotrophic and neuroprotective effect on dopaminergic system responding to the TBI insult.
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