Alterations of BDNF and NT-3 genes expression in the nucleus paragigantocellularis during morphine dependency and withdrawal
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Locus coeruleus
Neurochemical
Opiate
In rats, circulating corticosterone and insulin are involved in regulation of the hypothalamic neuropeptide Y (NPY) system, which in turn, is involved in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Since the HPA axis and stress responsivity is altered in diseases such as depression, we investigated interactions between the effects of stress and antidepressant drug treatment on arcuate nucleus and locus coeruleus NPY mRNA expressions using in-situ hybridization histochemistry. After acute (2 h) and repeated immobilization (2 h daily, for 14 days), plasma concentrations of corticosterone increased, and those of insulin decreased. The expression of NPY mRNA was significantly increased in the arcuate nucleus, but was unchanged in the locus coeruleus following acute and repeated immobilization. Adrenalectomized rats with systemic corticosterone replacement (ADX+CORT), whose corticosterone concentration was maintained at approximately 50-100 ng/ml during repeated stress, showed a decrease in plasma insulin and an increase in arcuate nucleus NPY mRNA similar to that observed in sham rats, suggesting that changes in NPY mRNA levels are more closely tied to circulating insulin than to circulating corticosterone. In contrast, locus coeruleus NPY mRNA expressions in ADX+CORT rats were significantly higher than those in sham rats after repeated stress. Desmethylimipramine (DMI) treatment for 24 days did not affect basal plasma concentrations of corticosterone or insulin, or arcuate nucleus NPY mRNA expressions, but significantly decreased basal levels of locus coeruleus NPY mRNA compared to saline-treated rats. After repeated immobilization (2 h daily, for 4 days), DMI significantly reduced the stress-induced rise in locus coeruleus NPY mRNA levels, but potentiated the stress-induced rise in arcuate nucleus NPY mRNA expression. These results demonstrate that: (1) the increase in arcuate nucleus NPY mRNA expressions in stressed rats closely follows the decrease in plasma concentrations of insulin; (2) increases in NPY mRNA expressions occur in the absence of changes in plasma corticosterone; and (3) desipramine treatment potentiated the effect of stress on arcuate nucleus NPY mRNA expressions, but blocked the repeated stress-induced increase in locus coeruleus NPY mRNA expressions. Thus, NPY mRNA expression in the arcuate nucleus and the locus coeruleus is sensitive to the effects of stress and to the antidepressant drug desipramine, but the arcuate nucleus NPY system is regulated by different mechanisms than the locus coeruleus NPY system. The results provide further evidence for the importance of circulating insulin in the regulation of the arcuate nucleus NPY system.
Locus coeruleus
Corticosterone
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We previously reported that brain-derived neurotrophic factor (BDNF) regulates both food intake and blood glucose metabolism in rodent obese diabetic models such as C57BL/KsJ-lepr(db)/lepr(db) (db/db) mice. To elucidate the effect of BDNF on glucose metabolism, we designed a novel pellet pair-feeding apparatus to eliminate the effect of appetite alteration on glucose metabolism. The apparatus was used to synchronize food intake precisely between BDNF-treated and vehicle-treated db/db mice. It was shown using this pellet pair-feeding apparatus that BDNF administered daily (20 mg x kg(-1) x day(-1)) to db/db mice significantly lowered blood glucose compared with pellet pair-fed db/db mice. To evaluate the effect of BDNF on insulin action, we used streptozotocin-induced type 1 diabetic mice. In this case, BDNF did not lower blood glucose concentration but rather enhanced the hypoglycemic action of insulin. In hyperglycemic db/db mice, pancreatic insulin content was reduced and glucagon content was increased compared with normoglycemic db/m mice. BDNF administered to db/db mice significantly restored both pancreatic insulin and glucagon content. Histological observations of aldehyde-fuchsin staining and immunostaining with anti-insulin indicated that insulin-positive pancreatic beta-cells were extensively regranulated by BDNF administration. We also studied the effect of BDNF on KK mice, normoglycemic animals with impaired glucose tolerance. In these mice, BDNF administration improved insulin resistance in the oral glucose tolerance test. To elucidate how blood glucose was metabolized in BDNF-treated animals, we investigated the effect of BDNF on the energy metabolism of db/db mice. Body temperature and oxygen consumption of the pellet pair-fed vehicle-treated mice were remarkably lower than the ad libitum-fed vehicle-treated mice. Daily BDNF administration for 3 weeks completely ameliorated both of the reductions. Finally, to clarify its action mechanism, the effect of intracerebroventricular administration of BDNF on db/db mice was examined. Here, a small dose of BDNF was found to be effective in lowering blood glucose concentration. This indicates that BDNF regulates glucose metabolism by acting directly on the brain.
Pancreatic Islets
Carbohydrate Metabolism
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Several neurobiological factors are related to opiate-use disorder (OUD), and among them, neurotrophins have a relevant role. Brain-derived neurotrophic factor (BDNF) is a central neurotrophin involved in many neuronal processes, and it has been related to several psychiatric diseases and addictive disorders. BDNF can be measured in plasma and serum; its levels may reflect BDNF concentrations in the central nervous system (CNS) and, indirectly, CNS processes. Hence, peripheral BDNF could be a biomarker in clinical practice. This manuscript explores the findings about peripheral BDNF and OUD in humans. Opiates induce neurotoxicity in the CNS, which may be correlated with modifications in BDNF expression. Thus, basal levels of peripheral BDNF in OUD patients may be altered, which could be modified with abstinence. Also, opiates may modify epigenetic processes that may be associated with peripheral concentrations of BDNF, and in this line, withdrawal could reflect recovering processes in the CNS. Additionally, treatment modifies the peripheral concentrations of BDNF, but the clinical implications of those changes are yet not elucidated. No specific conclusion can be performed and more investigation in this area is necessary to elucidate the real potential of peripheral BDNF as a biomarker.
Opiate
Neurotoxicity
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Successful peripheral nerve regeneration requires optimal conditions both in the macro-environment and micro-environment. Many methods have been used to improve the macro-environment for the regenerating nerve. However, much less is known about the micro-environment, and in particular the complex neurochemical interactions involved. Several neurotrophic factors have been shown to play an essential trophic role in the development, maintenance and regulation of neuronal function. These include nerve growth factor (NGF) and several recently identified members of the NGF family, namely brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5) and neurotrophin-6 (NT-6). In this review we summarize recent studies of the effects of these neurotrophins on neurones, especially their effects on motor neurones and their axonal outgrowth. We discuss prospects for the future and point out what remains to be understood about the role of neurotrophins to enhance peripheral nerve regeneration.
Neurochemical
Neurotrophin-3
Peripheral Nervous System
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Systemic administration of brain-derived neurotrophic factor (BDNF) decreases nonfasted blood glucose in obese, non-insulin-dependent diabetic C57BLKS-Lepr(db)/lepr(db) (db/db) mice, with a concomitant decrease in body weight. By measuring percent HbA1c in BDNF-treated and pair-fed animals, we show that the effects of BDNF on nonfasted blood glucose levels are not caused by decreased food intake but reflect a significant improvement in blood glucose control. Furthermore, once established, this effect can persist for weeks after cessation of BDNF treatment. Oral glucose tolerance tests were performed to examine the effects of BDNF on blood glucose control in the fasted state and after an oral glucose challenge. BDNF treatment normalized fasting blood glucose from initially hyperglycemic levels and also showed evidence for beneficial, although less marked, effects on the ability to remove exogenous glucose from blood. One means to lower fasting blood glucose is to reduce the glucose output of peripheral tissues that normally play a part in the maintenance of fasting hyperglycemia. Because the liver is the major endogenous source of glucose in blood during fasting, and because hepatic weight and glucose output are increased in type 2 diabetes, we evaluated the effects of BDNF on liver tissue. BDNF reduced the hepatomegaly present in db/db mice, in association with reduced liver glycogen and reduced liver enzyme activity in serum, supporting the possible involvement of liver tissue in the mechanism of action for BDNF.
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Neurochemical
Neurotrophin-3
Turnover
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The role of glial cell-line derived neurotrophic factor (GDNF) and neurotrophins in the development of locus coeruleus noradrenergic neurons was evaluated. We found that two neurotrophic factors previously reported to prevent the degeneration of lesioned adult central noradrenergic neurons, GDNF and neurotrophin 3 (NT3), do not play significant roles in the prenatal development of locus coeruleus noradrenergic neurons, as demonstrated by: (1)the lack of alterations in double Gdnf/Nt3 null mutant mice;and (2) the lack of survival-promoting effects of GDNF and/or NT3 in rat E13.5 primary cultures. In contrast, null mutant mice for TrkB, the tyrosine kinase receptor for brain-derived neurotrophic factor and neurotrophin 4, displayed a clear loss of locus coeruleus noradrenergic neurons. In accordance with this,treatment of rat E13.5 primary cultures with TrkB ligands prevented the early loss of noradrenergic neurons and maintained their survival for up to 6 days in vitro. Moreover, an additional 5-10-fold increase in the number of tyrosine hydroxylase positive noradrenergic neurons was detected after 12 hours in culture. This second effect of TrkB ligands involved neither proliferation nor survival, because the number of BrdU- or TUNEL-positive noradrenergic neurons did not change and the effect was elicited by delayed administration of either factor. Because TrkB ligands increased the number of tyrosine hydroxylase-positive cells expressing Phox2a, a paired homeodomain protein required for the development of locus coeruleus noradrenergic neurons, but did not affect the number of Phox2a-positive tyrosine hydroxylase-negative cells,our results suggest that the second effect of TrkB ligands may involve promoting or inducing a noradrenergic phenotype. In summary, our findings suggest that, unlike NT3 and GDNF, TrkB ligands are required and sufficient to promote the development of central noradrenergic neurons.
Locus coeruleus
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Locus coeruleus
Neurochemical
Opiate
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