Melatonin, the major hormone produced by the pineal gland, displays characteristic daily and seasonal patterns of secretion. These robust and predictable rhythms in circulating melatonin are strong synchronizers for the expression of numerous physiological processes in photoperiodic species. In mammals, the nighttime production of melatonin is mainly driven by the circadian clock, situated in the suprachiasmatic nucleus of the hypothalamus, which controls the release of norepinephrine from the dense pineal sympathetic afferents. The pivotal role of norepinephrine in the nocturnal stimulation of melatonin synthesis has been extensively dissected at the cellular and molecular levels. Besides the noradrenergic input, the presence of numerous other transmitters originating from various sources has been reported in the pineal gland. Many of these are neuropeptides and appear to contribute to the regulation of melatonin synthesis by modulating the effects of norepinephrine on pineal biochemistry. The aim of this review is firstly to update our knowledge of the cellular and molecular events underlying the noradrenergic control of melatonin synthesis; and secondly to gather together early and recent data on the effects of the nonadrenergic transmitters on modulation of melatonin synthesis. This information reveals the variety of inputs that can be integrated by the pineal gland; what elements are crucial to deliver the very precise timing information to the organism. This also clarifies the role of these various inputs in the seasonal variation of melatonin synthesis and their subsequent physiological function.

Generation of the Melatonin Endocrine Message in Mammals: A Review of the Complex Regulation of Melatonin Synthesis by Norepinephrine, Peptides, and Other Pineal Transmitters

Melatonin is a ubiquitous molecule present in almost every live being from bacteria to humans. In vertebrates, besides being produced in peripheral tissues and acting as an autocrine and paracrine signal, melatonin is centrally synthetized by a neuroendocrine organ, the pineal gland. Independently of the considered species, pineal hormone melatonin is always produced during the night and its production and secretory episode duration are directly dependent on the length of the night. As its production is tightly linked to the light/dark cycle, melatonin main hormonal systemic integrative action is to coordinate behavioral and physiological adaptations to the environmental geophysical day and season. The circadian signal is dependent on its daily production regularity, on the contrast between day and night concentrations, and on specially developed ways of action. During its daily secretory episode, melatonin coordinates the night adaptive physiology through immediate effects and primes the day adaptive responses through prospective effects that will only appear at daytime, when melatonin is absent. Similarly, the annual history of the daily melatonin secretory episode duration primes the central nervous/endocrine system to the seasons to come. Remarkably, maternal melatonin programs the fetuses' behavior and physiology to cope with the environmental light/dark cycle and season after birth. These unique ways of action turn melatonin into a biological time-domain-acting molecule. The present review focuses on the above considerations, proposes a putative classification of clinical melatonin dysfunctions, and discusses general guidelines to the therapeutic use of melatonin.

Melatonin as a hormone: new physiological and clinical insights

ContextThere is a paucity of effective, well-tolerated drugs available for
migraine prophylaxis.ObjectiveTo determine whether treatment with the angiotensin II receptor blocker
candesartan is effective as a migraine-prophylactic drug.Design and SettingRandomized, double-blind, placebo-controlled crossover study performed
in a Norwegian neurological outpatient clinic from January 2001 to February
2002.PatientsSixty patients aged 18 to 65 years with 2 to 6 migraine attacks per
month were recruited mainly from newspaper advertisements.InterventionsA placebo run-in period of 4 weeks was followed by two 12-week treatment
periods separated by 4 weeks of placebo washout. Thirty patients were randomly
assigned to receive one 16-mg candesartan cilexetil tablet daily in the first
treatment period followed by 1 placebo tablet daily in the second period.
The remaining 30 received placebo followed by candesartan.Main Outcome MeasuresThe primary end point was number of days with headache; secondary end
points included hours with headache, days with migraine, hours with migraine,
headache severity index, level of disability, doses of triptans, doses of
analgesics, acceptability of treatment, days of sick leave, and quality-of-life
variables on the Short Form 36 questionnaire.ResultsIn a period of 12 weeks, the mean number of days with headache was 18.5
with placebo vs 13.6 with candesartan (P = .001)
in the intention-to-treat analysis (n = 57). Some secondary end points also
favored candesartan, including hours with headache (139 vs 95; P<.001), days with migraine (12.6 vs 9.0; P<.001),
hours with migraine (92.2 vs 59.4; P<.001), headache
severity index (293 vs 191; P<.001), level of
disability (20.6 vs 14.1; P<.001) and days of
sick leave (3.9 vs 1.4; P = .01), although there
were no significant differences in health-related quality of life. The number
of candesartan responders (reduction of ≥50% compared with placebo) was
18 (31.6%) of 57 for days with headache and 23 (40.4%) of 57 for days with
migraine. Adverse events were similar in the 2 periods.ConclusionIn this study, the angiotensin II receptor blocker candesartan provided
effective migraine prophylaxis, with a tolerability profile comparable with
that of placebo.

/pdf/prophylactic-treatment-of-migraine-with-an-angiotensin-ii-2ecwm458tz.pdf

Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial.

CONTEXT
There is a paucity of effective, well-tolerated drugs available for migraine prophylaxis.


OBJECTIVE
To determine whether treatment with the angiotensin II receptor blocker candesartan is effective as a migraine-prophylactic drug.


DESIGN AND SETTING
Randomized, double-blind, placebo-controlled crossover study performed in a Norwegian neurological outpatient clinic from January 2001 to February 2002.


PATIENTS
Sixty patients aged 18 to 65 years with 2 to 6 migraine attacks per month were recruited mainly from newspaper advertisements.


INTERVENTIONS
A placebo run-in period of 4 weeks was followed by two 12-week treatment periods separated by 4 weeks of placebo washout. Thirty patients were randomly assigned to receive one 16-mg candesartan cilexetil tablet daily in the first treatment period followed by 1 placebo tablet daily in the second period. The remaining 30 received placebo followed by candesartan.


MAIN OUTCOME MEASURES
The primary end point was number of days with headache; secondary end points included hours with headache, days with migraine, hours with migraine, headache severity index, level of disability, doses of triptans, doses of analgesics, acceptability of treatment, days of sick leave, and quality-of-life variables on the Short Form 36 questionnaire.


RESULTS
In a period of 12 weeks, the mean number of days with headache was 18.5 with placebo vs 13.6 with candesartan (P =.001) in the intention-to-treat analysis (n = 57). Some secondary end points also favored candesartan, including hours with headache (139 vs 95; P<.001), days with migraine (12.6 vs 9.0; P<.001), hours with migraine (92.2 vs 59.4; P<.001), headache severity index (293 vs 191; P<.001), level of disability (20.6 vs 14.1; P<.001) and days of sick leave (3.9 vs 1.4; P =.01), although there were no significant differences in health-related quality of life. The number of candesartan responders (reduction of > or =50% compared with placebo) was 18 (31.6%) of 57 for days with headache and 23 (40.4%) of 57 for days with migraine. Adverse events were similar in the 2 periods.


CONCLUSION
In this study, the angiotensin II receptor blocker candesartan provided effective migraine prophylaxis, with a tolerability profile comparable with that of placebo.

Prophylactic Treatment of Migraine With an Angiotensin II Receptor Blocker

The production of the pineal hormone melatonin is synchronized with day-night cycle via multisynaptic pathway including suprachiasmatic nucleus linking several physiological functions to diurnal cycle. The recent data indicate that impaired melatonin production is involved in several cardiovascular pathologies including hypertension and ischemic heart disease. However, the mechanisms of melatonin effect on cardiovascular system are still not completely understood. The activation of melatonin receptors on endothelial and vascular smooth muscle cells and antioxidant properties of melatonin could be responsible for the melatonin effects on vascular tone. However, the data from in vitro studies are controversial making the explanation of the melatonin effect on blood pressure in vivo difficult. In vivo, melatonin also attenuates sympathetic tone by direct activation of melatonin receptors, scavenging free radicals or increasing NO availability in the central nervous system. The central and peripheral antiadrenergic action of chronic melatonin treatment might eliminate the mechanisms counter-regulating decreased blood pressure, providing thus additional cardioprotective mechanism. The extraordinary antioxidant activity and antilipidemic effects of melatonin may enhance the modulation of blood pressure by melatonin and probably play the most important role in the amelioration of target organ damage by chronic melatonin treatment. Further investigation of these mechanisms should provide novel knowledge about pathophysiological mechanisms of cardiovascular diseases, additional explanation for their circadian and seasonal variability and potentially generate new impulses for the development of therapeutic arsenal.

/pdf/blood-pressure-modulation-and-cardiovascular-protection-by-257qn6ci75.pdf

Blood pressure modulation and cardiovascular protection by melatonin: potential mechanisms behind.

We aimed to study the mechanisms and the significance of the influence exerted by the renin-angiotensin system (RAS) on the pineal melatonin production. Pineal melatonin and other indoles were determined by HPLC with electrochemical detection after angiotensin AT1-receptor blockade with Losartan in vivo or in cultured glands. N-acetyltransferase (NAT) activity was radiometricaly measured. To test the in vivo relevance of the local RAS, pineal melatonin and its indole precursors were determined in transgenic rats with inhibited production of angiotensinogen exclusively in astrocytes, TGR(ASrAOGEN). Tryptophan hydroxylase (TPH) and NAT mRNA levels were determined by real-time RT-PCR. Pineal melatonin content was significantly decreased by AT1-receptor blockade in vivo, in cultured glands and in TGR(ASrAOGEN) (35%, 32.4% and 17.5% from control, respectively). Losartan produced a significant decrease of pineal 5-hydroxytryptophan, serotonin, 5-hydroxyindole acetic acid and N-acetylserotonin in pineal cultures. Also, the pineal content of the precursor indoles in TGR(ASrAOGEN) rats was significantly lowered. The reduction of 5-hydroxytryptophan levels by 33-75% in both in vivo and in vitro studies suggests a decreased activity of TPH. Moreover, the TPH mRNA levels in TGR(ASrAOGEN) rats were significantly lower than control rats. On the other hand, NAT activity was unaffected by Losartan in pineal culture and its expression was not significantly different from control in TGR(ASrAOGEN) rats. Our results demonstrate that a local pineal RAS exerts a tonic modulation of indole synthesis by influencing the activity of TPH via AT1-receptors.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.0022-3042.2001.00701.x

Locally synthesized angiotensin modulates pineal melatonin generation.

Tryptophan hydroxylase is modulated by L-type calcium channels in the rat pineal gland

The presence of high voltage-activated calcium channels in the rat pineal gland is well known. However, their role in pineal metabolism is not completely understood and is even controversial. Better to understand this matter, we investigated the effects of L-, N- or P/Q-type calcium channel blockers (nifedipine, omega-conotoxin GVIA, omega-agatoxin IVA, respectively) on melatonin content and arylalkylamine-N-acetyltransferase activity of denervated rat pineal glands kept for 48 h in culture and stimulated with norepinephrine. Melatonin was measured by high performance liquid chromatography with electrochemical detection and arylalkylamine-N-acetyltransferase activity was quantified by radiometric assay. Pre-incubation with any of these high voltage-activated calcium channel blockers reduced the melatonin production induced by norepinephrine although arylalkylamine-N-acetyltransferase activity was reduced only by the N-type calcium channel antagonist, omega-conotoxin GVIA. The results indicate that calcium influx through L-, N- or P/Q-type of high voltage-activated calcium channels is necessary for the full expression of the metabolic process leading to melatonin synthesis in the rat pineal glands. However, the mechanisms involved in this process are different for the L- or P/Q- and N-type calcium channels.

Roseli Barbosa

Papers

Locally synthesized angiotensin modulates pineal melatonin generation.

Tryptophan hydroxylase is modulated by L-type calcium channels in the rat pineal gland

Effects of the blockade of high voltage-activated calcium channels on in vitro pineal melatonin synthesis.

Papel do cálcio na síntese de melatonina pela glândula pineal de ratos