As a classic neurotransmitter in the brain, norepinephrine (NE) also is an important modulator to other neuronal systems. Using primary cultures from rat ventral mesencephalon (VM) and dopaminergic cell line MN9D, the present study examined the neuroprotective effects of NE and its effects on the expression of tyrosine hydroxylase (TH). The results showed that NE protected both VM cultures and MN9D cells against 6-hydroxydopamine-caused apoptosis, with possible involvement of adrenal receptors. In addition, treatment with NE upregulated TH protein levels in dose- and time-dependent manner. Further experiments to investigate the potential mechanisms underlying this NE-induced upregulation of TH demonstrated a marked increase in protein levels of the brain-derived neurotrophic factor (BDNF) and the phosphorylated extracellular signal-regulated protein kinase 1 and 2 (pERK1/2) in VM cultures treated with NE. In MN9D cells, a significantly increase of TH and pERK1/2 protein levels were observed after their transfection with BDNF cDNA or exposure to BDNF peptides. Treatment of VM cultures with K252a, an antagonist of the tropomyosin-related kinase B, blocked the upregulatory effects of NE on TH, BDNF and pERK1/2. Administration of MEK1 & MEK2 inhibitors also reversed NE-induced upregulation of TH and pERK1/2. Moreover, ChIP assay showed that treatment with NE or BDNF increased H4 acetylation in the TH promoter. These results suggest that the neuroprotection and modulation of NE on dopaminergic neurons are mediated via BDNF and MAPK/ERK pathways, as well as through epigenetic histone modification, which may have implications for the improvement of therapeutic strategies for Parkinson's disease.

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Distribution of prolactin-releasing peptide-like immunoreactivity (PrRP- LI) was investigated in the rat medulla with the use of a rabbit polyclonal antiserum against the human PrRP-31 peptide. PrRP-positive neurons were noted mainly in two areas of the caudal medulla: ventrolateral reticular formation and commissural nucleus of the nucleus of the solitary tract (NTS), corresponding to the A1 and A2 areas. PrRP-LI neurons were absent in the medulla rostral to the area postrema. Double-labeling the sections with PrRP antisera and tyrosine hydroxylase (TH) monoclonal antibodies revealed extensive colocalization of PrRP- and TH-like immunoreactivity (TH-LI) in neurons of the A1 and A2 areas. Our results show that PrRP-LI is expressed in a population of A1 and A2 noradrenergic neurons of the rat caudal medulla.

This study investigated the effects of the pharmacological manipulation of noradrenergic activities on dopaminergic phenotypes in aged rats. Results showed that the administration of L-threo-3,4-dihydroxyphenylserine (L-DOPS) for 21 days significantly increased the expression of tyrosine hydroxylase (TH) and dopamine transporter (DAT) in the striatum and substantia nigra (SN) of 23-month-old rats. Furthermore, this treatment significantly increased norepinephrine/DA concentrations in the striatum and caused a deficit of sensorimotor gating as measured by prepulse inhibition (PPI). Next, old rats were injected with the α2-adrenoceptor antagonist 2-methoxy idazoxan or β2-adrenoceptor agonist salmeterol for 21 days. Both drugs produced similar changes of TH and DAT in the striatum and SN. Moreover, treatments with L-DOPS, 2-methoxy idazoxan, or salmeterol significantly increased the protein levels of phosphorylated Akt in rat striatum and SN. However, although a combination of 2-methoxy idazoxan and salmeterol resulted in a deficit of PPI in these rats, the administration of 2-methoxy idazoxan alone showed an opposite behavioral change. The in vitro experiments revealed that treatments with norepinephrine markedly increased mRNAs and proteins of ATF2 and CBP/p300 and reduced mRNA and proteins of HDAC2 and HDAC5 in MN9D cells. A ChIP assay showed that norepinephrine significantly increased CBP/p300 binding or reduced HDAC2 and HDAC5 binding on the TH promoter. The present results indicate that facilitating noradrenergic activity in the brain can improve the functions of dopaminergic neurons in aged animals. While this improvement may have biochemically therapeutic indication for the status involving the degeneration of dopaminergic neurons, it may not definitely include behavioral improvements, as indicated by using 2-methoxy idazoxan only.

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Investigamos os efeitos do treinamento físico (T) sobre a densidade da tirosina hidroxilase (TH) em arteríolas e adrenais (respostas neuro-hormonais). SHR machos foram treinados (55% da capacidade máxima) ou mantidos sedentários (S). Após o registro da PA e FC basais, foram anestesiados para obtenção dos tecidos (músculos locomotores: sóleo, gastrocnêmio, grácil; não-locomotor: temporal; rins e supra-renais) para o Western Blot ou imunohistoquímica. O T aumentou a capacidade física (+77%) e reduziu PA e FC (-6% e -10%, p<0.05). Houve aumento da TH imunorreatividade nos músculos locomotores (+57%, p<0.05), com aumento discreto no temporal (+24%, p>0.05), sem alteração nos rins. Houve normalização da razão parede/luz apenas nas arteríolas de músculos locomotores, sem alteração da TH nas supra-renais. O T aumenta a síntese/armazenamento da noradrenalina nas arteríolas musculares esqueléticas (resposta neural), uma compensação à redução da razão p/l para manutenção do fluxo sanguíneo local. A não alteração de TH no temporal sugere que a resposta neural é modulada por fatores locais / We investigated the effects of training (T) on tyrosine hydroxylase (TH) density in arterioles and adrenals (neuro-hormoral responses). Male SHR were submitted to treadmill T (55% of maximal capacity) or kept sedentary (S). After AP and HR recordings, rats were anesthetized and tissues (soleus, gastrocnemius red, gracilis = locomotor; temporalis = non-locomotor muscle; kidney and adrenals) collected for Western Blot and immunohistochemistry. T improved treadmill performance (+77%) and reduced AP and HR (-6% and -10%, p<0.05). TH immunoreactivity was increased in locomotor muscles (+57%, p<0.05) with smaller changes on temporalis (+24%, p>0.05) without any change on kidneys. Enlarged arterioles wall/lumen ratio was reduced only in locomotor muscles; there was no change on adrenals TH content. T increases noradrenaline synthesis/storage on skeletal muscles arterioles, which represents a compensatory neural response to T-induced structural remodeling in order to maintain a near normal local flow. Absence of changes on temporalis TH suggests that neural response is modulated by local factors

Investigamos os efeitos do treinamento físico (T) sobre a densidade da tirosina hidroxilase (TH) em arteríolas e adrenais (respostas neuro-hormonais). SHR machos foram treinados (55% da capacidade máxima) ou mantidos sedentários (S). Após o registro da PA e FC basais, foram anestesiados para obtenção dos tecidos (músculos locomotores: sóleo, gastrocnêmio, grácil; não-locomotor: temporal; rins e supra-renais) para o Western Blot ou imunohistoquímica. O T aumentou a capacidade física (+77%) e reduziu PA e FC (-6% e -10%, p<0.05). Houve aumento da TH imunorreatividade nos músculos locomotores (+57%, p<0.05), com aumento discreto no temporal (+24%, p>0.05), sem alteração nos rins. Houve normalização da razão parede/luz apenas nas arteríolas de músculos locomotores, sem alteração da TH nas supra-renais. O T aumenta a síntese/armazenamento da noradrenalina nas arteríolas musculares esqueléticas (resposta neural), uma compensação à redução da razão p/l para manutenção do fluxo sanguíneo local. A não alteração de TH no temporal sugere que a resposta neural é modulada por fatores locais / We investigated the effects of training (T) on tyrosine hydroxylase (TH) density in arterioles and adrenals (neuro-hormoral responses). Male SHR were submitted to treadmill T (55% of maximal capacity) or kept sedentary (S). After AP and HR recordings, rats were anesthetized and tissues (soleus, gastrocnemius red, gracilis = locomotor; temporalis = non-locomotor muscle; kidney and adrenals) collected for Western Blot and immunohistochemistry. T improved treadmill performance (+77%) and reduced AP and HR (-6% and -10%, p<0.05). TH immunoreactivity was increased in locomotor muscles (+57%, p<0.05) with smaller changes on temporalis (+24%, p>0.05) without any change on kidneys. Enlarged arterioles wall/lumen ratio was reduced only in locomotor muscles; there was no change on adrenals TH content. T increases noradrenaline synthesis/storage on skeletal muscles arterioles, which represents a compensatory neural response to T-induced structural remodeling in order to maintain a near normal local flow. Absence of changes on temporalis TH suggests that neural response is modulated by local factors