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The nervous system plays a key role in the regulation of neuroendocrine axes and, in turn, the released neurohormones modulate the activity of different brain regions. Neurodegenerative diseases, which are known to affect specific neuronal populations, may provoke neuroendocrine dysfunctions that alter the intimate relationship between both systems. In addition, these modifications may influence the progression of the neurodegenerative process. In the present review, we summarise some of the endocrine changes characterising three major neurodegenerative diseases: Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Special attention is focused on the contribution of disease transgenic models to elucidate such alterations.

The biological effects of pituitary adenylate cyclase-activating peptide (PACAP) 27 and 38 on peptide secretion and gene regulation were studied in the mouse corticotrope-derived cell line AtT20. Treatment of these cells with PACAP 27/38 led to a dose-dependent increase in cAMP content and ACTH accumulation in the medium with an apparent ED50 value close to 10(-9) M. The genomic effects of PACAP were first investigated by using a reporter gene containing a cAMP responsive element (CRE: TGACGTCA) PACAP 27/38 stimulate transcription from this construction and the effect is further increased when cells are cotreated with the phosphodiesterase inhibitor rolipram. Furthermore, we show by measuring nuclear heterologous proopiomelanocortin (POMC) RNA levels or by using a reporter gene containing the POMC promoter region, that PACAP stimulates POMC transcription. This transcriptional stimulation is mediated by the cAMP-dependent protein kinase (PKA) since genetic inactivation of PKA by a dominant inhibitory mutant of this enzyme completely abolished the effect of PACAP on POMC transcription. Finally, we show that the transcriptional stimulation of POMC by PACAP is repressed by the glucocorticoid receptor agonist dexamethasone. Taken together, these data suggest that PACAP is a hypophysiotropic hormone that exert similar if not identical functions as corticotropin-releasing hormone (CRH) on corticotrope cells.

The nervous system plays a key role in the regulation of neuroendocrine axes and, in turn, the released neurohormones modulate the activity of different brain regions. Neurodegenerative diseases, which are known to affect specific neuronal populations, may provoke neuroendocrine dysfunctions that alter the intimate relationship between both systems. In addition, these modifications may influence the progression of the neurodegenerative process. In the present review, we summarise some of the endocrine changes characterising three major neurodegenerative diseases: Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Special attention is focused on the contribution of disease transgenic models to elucidate such alterations.

In this study, we examined the effects of oxidative stress on a nitric oxide (NO)-regulated neuroendocrine function, the release of arginine vasopressin (AVP) by the hypothalamo-neurohypophyseal axis. Treatment of mouse-isolated hypothalami and neurointermediate lobes () with H2O2 increased AVP release. This effect was inhibited by copper-zinc superoxide dismutase-1 (SOD1) analogs. By measuring cGMP accumulation as an indicator of biologically active NO, we found that H2O2 treatment decreased cGMP formation in both hypothalami and . We have previously shown that NO inhibits AVP release by a cGMP-independent mechanism. Given that H2O2 stimulated AVP release, while it reduced cGMP production, our findings strongly suggest that oxidative damage affects neurosecretion by reducing NO availability. To test whether such a mechanism may operate under pathological conditions with pronounced oxidative stress, we compared neurosecretion in wild-type and transgenic mice carrying a mutated form of SOD1 associated with human familial amyotrophic lateral sclerosis. Reminiscent of the data obtained from H2O2-treated tissues, hypothalami and from SOD1 mutants displayed decreased cGMP accumulation and increased AVP release, compared with tissues from wild-type littermates. Since neuronal NO synthase expression was not modified, we conclude that the perturbed free radical metabolism associated with the SOD1 mutation is likely to trap NO, and thereby alter neurosecretion, a mechanism that can be exacerbated in specific physiopathological conditions.

The effect of histamine on messenger ribonucleic acid levels encoding proenkephalin A (mRNAenk) was studied in serum-free cultures of bovine adrenal chromaffin cells. Histamine (10–7

The effects of dopamine on proopiomelanocortin (POMC) gene expression were compared in primary cultures of the anterior and intermediate lobes of the rat pituitary. A single-stranded POMC complementary DNA was used to quantitate POMC messenger RNA levels. Treatment with dopamine (1 µM) for 48 h reduced POMC messenger RNA levels in the intermediate lobe by 77%, but had no effect on POMC gene expression in the anterior lobe. Dopamine D2 receptors were implicated in the response, as bromocriptine (100 nM) reproduced the dopamine inhibition. The responses to dopamine and bromocriptine were antagonized by haloperidol (10 µM). The decrease in POMC messenger RNA levels was dose dependent with ED50 values of about 50 and 0.1 nM for dopamine and bromocriptine, respectively. The accumulation of POMC-derived peptides, β-endorphin and α-melanocyte-stimulating hormone, over 2 days was measured by radioimmunnoassay and was shown to parallel the changes in POMC synthesis. The dopamine-induced inhibition of intermediate lobe POMC synthesis was unaffected by isoprenalin (5 µM) and corticotropin-releasing factor (10 nM), although these treatments had stimulatory effects when tested alone. Activating adenylate cyclase with forskolin (1 µM) or treatment with 8-bromocyclic adenosine monophosphate (1 mM) doubled POMC messenger RNA levels, and, when tested against these stimuli, bromocriptine still produced a 30% inhibition of POMC gene expression. These observations suggest that D2 receptor induced inhibition of POMC gene expression is not only mediated by a decrease in cyclic adenosine monophosphate levels. When cells were pretreated with pertussis toxin (100 ng/ml), the bromocriptine-induced inhibition was almost completely lost, suggesting that the dopaminergic inhibition is mediated by guanosine triphosphate binding proteins.

The inhibitory action of gamma-aminobutyric acid (GABA) on prolactin (PRL) messenger ribonucleic acid (mRNA) levels was studied in vitro in rat anterior pituitary cells in culture and in intact rats in vivo. PRL mRNA levels were determined by hybridization of cytoplasmic RNA with a radiolabelled deoxyribonucleic acid probe complementary to rat PRL mRNA. Incubation of anterior pituitary cultures with GABA (10-100 microM) produced a dose-dependent decrease in PRL mRNA levels with half-maximal inhibition near 1 microM. The effect was time dependent and reversible after drug withdrawal. Inhibition by GABA was antagonized by bicuculline (10 microM) and mimicked by the GABAA receptor agonists muscimol and isoguvacine, but not with the GABAB agonist baclofen, indicating the involvement of GABAA receptors in the accumulation of PRL mRNA. To investigate the role of endogenous GABA on PRL biosynthesis in vivo, GABA levels were raised by using the GABA transaminase blockers vinyl GABA and ethanolamine-O-sulfate. Injection of vinyl GABA into rats (100 or 800 mg/kg every 2nd day) resulted in a dose- and time-dependent decrease in PRL mRNA levels in rat adenohypophysis. Similar results were obtained by addition of ethanolamine-O-sulfate to the drinking water (5 mg/ml, 250 mg/day). This treatment resulted in a rapid decrease of circulating PRL levels. This was followed by a delayed decrease in PRL mRNA concentrations in the adenohypophysis leading to a transient increase in hormone levels in the anterior pituitary. The results indicate that GABA has an inhibitory role on PRL secretion and PRL gene expression by a direct action at GABAA receptors on pituitary lactotrophs.