Higher levels of proinflammatory cytokines are found in Parkinson's disease (PD) patient's brains and inflammation is thought to be a major contributor to the neurodegeneration. During the inflammatory process, microglial release of proinflammatory cytokines act on the endothelium of blood-brain barrier (BBB) cells to stimulate upregulation of adhesion molecules. Consequently, this upregulation leads to the recruitment of passing T cells and monocytes, which express the counter receptors, that then go on to release more cytokines [Whitton, P.S., 2007. Inflammation as a causative factor in the aetiology of Parkinson's disease, Br. J. Pharmacol. 50, 963-976; Kortekaas, R., Leenders, K.L., Van Oostrom, J.C., Vaalburg, W., Bart, J., Willemsen, A.T., Hendrikse, N.H., 2005. Blood-brain barrier dysfunction in parkinsonian midbrain in vivo, Ann. Neurol. 57, 176-179]. In addition, a systemic inflammatory response results in the production of cytokines which circulate in the blood and communicate with neurons within the brain. Thus, a central inflammatory reaction interacts with peripheral blood mononuclear cells (PBMCs) modulating immune activity. The present study investigates levels of production and expression of cyto/chemokines by PBMCs in PD patients. Basal and LPS-induced levels of MCP-1, RANTES, MIP-1alpha, IL-8, IFNgamma, IL-1beta and TNFalpha were significantly higher in PD patients than in HC subjects (p<0.001), as determined by RT-PCR and Elisa methods. Cyto/chemokine levels were significantly correlated with UPDRS III and H/Y stage (p<0.001). The Pearson's correlation coefficient (R) was also used to assess the strength of the relationship between NF-kappaBp65 levels and all studied cyto/chemokines and between NF-kappaBp65, UPDRS III and H/Y score in PD patients. The overall results strengthen and extend the knowledge of the peripheral dysregulation in the cytokine network associated with PD.

Peripheral cytokines profile in Parkinson's disease

Norepinephrine (NE) and dopamine (DA) turnover rates were measured in the medial preoptic area (MPO) and in the anterior and posterior mediobasal hypothalamus (AMBH and PMBH) in groups of rats subjected to various endocrinological manipulations. NE turnover in the MPO was high in proestrous, ovariectomized, ovariectomized estrogenprimed, and ovariectomized, estrogen-primed, progesteronetreated rats when the experiments were carried out during afternoon hours. Diestrous rats had low NE turnover rates in the MPO. The NE turnover rate was also low when measured in ovariectomized, estrogen-primed animals decapitated in the morning. These turnover rates parallel low serum LH levels. NE turnover in the AMBH and PMBH was low in diestrous and ovariectomized animals during afternoon hours and was also low in ovariectomized estrogen-primed rats during morning hours. High NE turnover rates in these structures were measured in proestrous, ovariectomized, estrogen-primed and estrogenprimed, progesterone-treated rats k...

Norepinephrine and dopamine turnover rates in the medial preoptic area and the mediobasal hypothalamus of the rat brain after various endocrinological manipulations.

Decreased dopamine turnover in the median eminence in response to suckling in the lactating rat

Ovarian steroids influence the activity of neuroendocrine dopaminergic neurons

The role of the paraventricular nucleus (PVN) in mediating acute stimulatory PRL responses was investigated in conscious male rats. Electrolytic lesions, verified histologically at autopsy, were stereotaxically made in the PVN region, and sham lesions were made in control rats. Blood was obtained through a chronically indwelling catheter in the right atrium. PVN-lesioned (PVL) rats showed significantly lower T3 levels 1 week after surgery (<34.4 ng/dl) compared with sham (mean ± SEM, 91.2 ± 5.0 ng/dl) and intact (86.8 ± 2.0 ng/dl) animals, verifying a lesion in the PVN. T3 was restored to normal (95.6 ± 1.8 ng/dl) by daily sc administration of T4 (10 Mg/kg BW) for at least 4 days before the day of the experiments. Basal PRL levels in PVL rats did not differ significantly from those in control or sham-lesioned animals. In response to restraint stress, plasma PRL levels of PVL rats did not rise, in contrast to marked elevation in PRL in sham and intact rats [PRL levels (mean ± SEM; nanograms per ml), basal ...

Paraventricular Nucleus Mediates Prolactin Secretory Responses to Restraint Stress, Ether Stress, and 5-Hydroxy-L-Tryptophan Injection in the Rat

The effects of a catecholamine synthesis inhibitor, alpha-methyl-p-tyrosine (alpha-MT), on the accumulation of newly synthesized brain catecholamines and plasma prolactin concentration were studied in lactating rats. [3H]tyrosine was administered to rats 10 minutes before decapitation, and the rate of its incorporation into [3H]dopamine and [3H]norepinephrine was measured in whole brain. Injection of alpha-MT (3.15--12.50 mg/kg) via a carotid cannula increased plasma prolactin levels and decreased the accumulation of newly synthesized brain catecholamines in nonsuckled, lactating rats compared to rats injected with .9% saline solution. Mother rats pretreated with saline solution were suckled for 20 minutes by pups which previously were separated from the mother rats for 5 hours. This treatment resulted in significantly increased plasma prolactin levels compared to nonsuckled controls. In rats pretreated with alpha-MT for 20 minutes, suckling resulted in a further increase in plasma prolactin levels which was significantly greater than the increase caused by suckling or alpha-MT alone. These results suggest that inhibition or catecholamine synthesis had a facilitatory effect on the brain mechanisms responsible for prolactin release in response to suckling.

Potentiation of suckling-induced release of prolactin by inhibition of brain catecholamine synthesis.

A series of experiments was performed on estrogen/progesterone-treated, ovariectomized rats to determine the site of the inhibitory effect of L-3,4- dihydroxyphenylalanine (L-dopa) on prolactin release. After intraarterial injection of L-[3H]dopa (150 μCi), [3H]norepinephrine ([3H]NE), [3H]dopamine ([3H]DA), and L-[3H]dopa were found in the hypothalamus and anterior pituitary. Intra-arterial injection of L-dopa (2, 5, or 10 mg/kg) produced a dose-related inhibition of prolactin release. The magnitude and the duration of inhibition of prolactin release were greater with increasing doses of L-dopa. Hypothalamic concentrations of endogenous DA were significantly increased 30 min after L-dopa (10 mg/kg) and were correlated with decreased serum prolactin levels at this time. Hypothalamic NE content was not affected. L-α-Methyldopa hydrazine, 20 mg/kg (Mk 486), a peripheral aromatic L-amino acid decarboxylase inhibitor, injected 30 min before L-[3H]dopa injection, increased the concentration of L-[3H]dopa in th...

L-3,4-Dihydroxyphenylalanine (L-Dopa) as an Inhibitor of Prolactin Release

The effects of estrogen (E) and progesterone (P) on synthesis rates and endogenous levels of hypothalamic norepinephrine (NE) and dopamine (DA) were determined in individual ovariectomized (OVX) rats. 3H-tyrosine (3H-T) was injected intra-arterially and the rate of its incorporation into 3H-DA and 3H-NE was determined at 10, 15, 30, and 45 min. Steroid treatment for 2 days effectively decreased plasma LH levels and elevated plasma prolactin (Prl) levels while endogenous levels of NE and DA were not affected. NE synthesis was not affected by steroid treatment. A significant increase in DA synthesis was correlated with low plasma LH levels, suggesting that DA inhibits LH release. The elevated plasma Prl levels seen in steroid-treated rats were correlated with increased DA synthesis in the hypothalamus. This may indicate that elevated plasma Prl levels stimulate dopaminergic neurons in a short-loop negative feedback fashion.

L. A. Carr

Papers

Potentiation of suckling-induced release of prolactin by inhibition of brain catecholamine synthesis.

L-3,4-Dihydroxyphenylalanine (L-Dopa) as an Inhibitor of Prolactin Release

Plasma luteinizing hormone and prolactin levels and hypothalamic catecholamine synthesis in steroid-treated ovariectomized rats.