Primary Gamma Knife Radiosurgery for pineal region tumors: A systematic review and pooled analysis of available literature with histological stratification.

Pineal region tumors (PTs) represent extremely rare pathologies, characterized by highly heterogeneous histological patterns. Most of the available evidence for Gamma Knife radiosurgical (GKSR) treatment of PTs arises from multimodal regimens, including GKSR as an adjuvant modality or as a salvage treatment at recurrence. We aimed to gather existing evidence on the topic and analyze single-patient-level data to address the efficacy and safety of primary GKSR. This is a systematic review of the literature (PubMed, Embase, Cochrane, Science Direct) and pooled analysis of single-patient-level data. A total of 1054 original works were retrieved. After excluding duplicates and irrelevant works, we included 13 papers (n = 64 patients). An additional 12 patients were included from the authors' original series. A total of 76 patients reached the final analysis; 56.5% (n = 43) received a histological diagnosis. Confirmed lesions included pineocytoma WHO grade I (60.5%), pineocytoma WHO grade II (14%), pineoblastoma WHO IV (7%), pineal tumor with intermediate differentiation WHO II/III (4.7%), papillary tumor of pineal region WHO II/III (4.7%), germ cell tumor (2.3%), neurocytoma WHO I (2.3%), astrocytoma WHO II (2.3%) and WHO III (2.3%). Presumptive diagnoses were achieved in the remaining 43.5% (n = 33) of cases and comprised of pineocytoma (9%), germ cell tumor (6%), low-grade glioma (6%), high-grade glioma (3%), meningioma (3%) and undefined in 73%. The mean age at the time of GKSR was 38.7 years and the mean lesional volume was 4.2 ± 4 cc. All patients received GKSR with a mean marginal dose of 14.7 ± 2.1 Gy (50% isodose). At a median 36-month follow-up, local control was achieved in 80.3% of cases. Thirteen patients showed progression after a median time of 14 months. Overall mortality was 13.2%. The median OS was not reached for all included lesions, except high-grade gliomas (8mo). The 3-year OS was 100% for LGG and pineal tumors with intermediate differentiation, 91% for low-grade pineal lesions, 66% for high-grade pineal lesions, 60% for germ cell tumors (GCTs), 50% for HGG, and 82% for undetermined tumors. The 3-year progression-free survival (PFS) was 100% for LGG and pineal intermediate tumors, 86% for low-grade pineal, 66% for high-grade pineal, 33.3% for GCTs, and 0% for HGG. Median PFS was 5 months for HGG and 34 months for GCTs. The radionecrosis rate was 6%, and cystic degeneration was observed in 2%. Ataxia as a presenting symptom strongly predicted mortality (odds ratio [OR] 104, p = .02), while GCTs and HGG histology well predicted PD (OR: 13, p = .04). These results support the efficacy and safety of primary GKSR treatment of PTs. Further studies are needed to validate these results, which highlight the importance of the initial presumptive diagnosis for choosing the best therapeutic strategy.

Pineal region tumours in the sitting position: how I do it.

BACKGROUND: Pineal region tumours remain challenging neurosurgical pathologies. METHODS: Detailed anatomical knowledge of the posterior incisural space and its variations is critical. An opaque arachnoidal membrane seals the internal cerebral and basal veins, leading to thalamic, basal ganglia, mesencephalic/pontine infarctions if injured. Medium-size tumours can be removed en-bloc with all traction/manipulation applied on the tumour side, virtually without contact of ependymal surfaces of the pulvinars or third ventricle. Sacrifice of the cerebello-mesencephalic fissure vein may be required. CONCLUSIONS: The sitting position offers superior anatomical orientation and remains safe with experienced teams. Meticulous microsurgical techniques and detailed anatomical knowledge are likely to secure safe outcomes.

The effects of melatonin on the healing of burn wounds in pinealectomized rats.

BACKGROUND: The present study aims to investigate the favorable effects of melatonin on burn wound healing in rats. METHODS: In this study, forty Wistar-albino-type male rats were divided into four groups. Group 1 was the control group, Group 2 rats were treated using exogenous melatonin, Group 3 rats were pinealectomized, and Group 4 rats were pinealectomized then treated with exogenous melatonin. In all groups, a deep second-degree burn was created on the backs of the rats with a metal plate heated in boiling water. We monitored the progress of burn healing for seven days. At the end of them, we evaluated hydroxyproline levels, type III collagen, edema, inflammatory infiltration, congestion, vascular proliferation, fibrosis, the thickness of the zone of stasis and the epithelium to assess the progress of healing. RESULTS: The zone of stasis was less thick in Group 2 than the other groups (p=0.009). Type III collagen dyeing (p=0.031), fibrosis (p=0.011) and edema (p=0.031) were higher in Group 2 than the other groups. Congestion was higher in the control group than Group 4 (p=0.031). Other evaluated parameters showed no significant differences among the groups. CONCLUSION: In this study, it was noted that once total melatonin levels exceeded a certain threshold, a preventive effect was exerted on burn wound damage progression by reducing the zone of stasis. Melatonin may also prevent the development of hypertrophic scarring. Melatonin may be a potential therapeutic option that can supplement traditional treatment in burn wounds; however, further studies with higher doses of exogenous melatonin administered over longer periods are needed to further evaluate the effects noted in this study.

Melatonin modulates monochromatic light-induced melatonin receptor expression in the hypothalamus of chicks.

To study the mechanism of the effect of monochromatic light on physiological function in chicken, a total of 192 newly hatched chicks were randomly divided into intact, sham-operated and pinealectomy groups then exposed to white light (WL), red light (RL), green light (GL) and blue light (BL) using a light-emitting diode (LED) system for two weeks. At P14, the hypothalami were immediately collected for immunohistochemical staining of melatonin receptor subtypes (Mel1a and Mel1b) and detection of Mel1a and Mel1b expressions using RT-PCR and western blot. Immunohistochemical staining of the hypothalamus showed that the Mel1a-ir cells were distributed in the preoptic area (POA), nucleus preopticus periventricularis (POP) and suprachiasmatic nuclei (SCN), and the Mel1b-ir cells were presented in the POA and SCN. Analysis of RT-PCR and western blot showed that the mRNA and protein levels of Mel1a and Mel1b in the hypothalamus of chick exposed to GL were increased by 10.7-29.3%, 9.18-35.9% and 8.97-27.3% compared to those in the chicks exposed to WL (P=0.029-0.002), RL (P=0.027-0.001) and BL (P=0.038-0.007) in the intact group, respectively. After pinealectomy, however, these parameters decreased and there were no significant differences among the WL, RL, GL and BL groups. These findings suggested that melatonin plays a critical role in GL illumination-enhanced Mel1a and Mel1b expressions in the hypothalamus of chicks.

Pinealectomy abolishes circadian behavior and interferes with circadian clock gene oscillations in brain and liver but not retina in a migratory songbird.

In songbirds, the pineal gland is part of the multi-oscillatory circadian timing system, with participating component oscillators in the eyes and hypothalamus. This study investigated the role of the pineal gland in development of the nighttime migratory restlessness (Zugunruhe) and generation of circadian gene oscillations in the retina, brain and liver tissues in migratory redheaded buntings (Emberiza bruniceps). Pinealectomized (pinx) and sham-operated buntings entrained to short days (8h light: 16h darkness, 8L:16D) were sequentially exposed for 10days each to stimulatory long days (13L: 11D) and constant dim light (LLdim; a condition that tested circadian rhythm persistence). Whereas activity-rest pattern was monitored continuously, the mRNA expressions of clock genes (bmal1, clock, npas2, per2, cry1, rorα, reverα) were measured in the retina, hypothalamus, telencephalon, optic tectum and liver tissues at circadian times, CT, 1, 6, 13, 17 and 21 (CT 0, activity onset) on day 11 of the LLdim. The absence of the pineal gland did not affect the development of long-day induced Zugunruhe but caused decay of the circadian rhythm in Zugunruhe as well as the clock gene oscillations in the hypothalamus, but not in the retina. Further, there were variable effects of pinealectomy in the peripheral brain and liver tissue circadian gene oscillations, notably the persistence of per 2 and cry1 (optic tectum), rorα (telencephalon) and npas2 (liver) mRNA oscillations in pinx birds. We suggest the pineal gland dependence of the generation of circadian gene oscillations in the hypothalamus, not retina, and peripheral brain and liver tissues in migratory redheaded buntings.

[Participation of pineal gland in antistressor activity of adaptogenic drugs].

Chronic stress produces some morphological changes in rats, including thymus weight reduction, adrenal hypertrophy, and peptic ulcers in stomach. Repeated administration of phytoadaptogenic drugs (ginseng and bilobil) decreased these stress-induced disorders. The antistressor activity of drugs was attenuated upon by removal of the pineal gland. Histochemical and morphometric investigation of pineal tissues in stressed animals showed that that the pharmacological effect was accompanied by increasing functional activity of the pineal gland. It is suggested that pineal mobilization may participate in antistressor activity of phytoadaptogenic drugs.

[Chronotropic properties of adaptogenic drugs].

Adaptogenic agents of hormonal (melatonin) and plant origin (ginseng and bilobil) produce optimizing effect on circadian rhythm of locomotion and on the temporal dynamics of forced swimming in intact and false-operated rats. Melatonin exhibits the most expressed impact on behavior of animals. After the removal of the pineal gland, these effects of investigated drugs were significantly decreased. It is suggested that the pineal gland may take part in the chronotropic activity of adaptogenic drugs.

Combined usage of estrogen and melatonin restores bladder contractility and reduces kidney and bladder damage in ovariectomized and pinealectomized rat.

OBJECTIVE: The incidence of urinary bladder disturbances and renal structural changes and functional decline are found to increase with age. METHODS: We investigated the effect of melatonin treatment in addition to estrogen replacement therapy in pinealectomized (Px) and ovariectomized (Ovx) rats. 56 female Wistar rats were divided into seven groups, each containing eight animals: Sham, (Ovx), (Px), Px+Ovx, Px+Ovx receiving estrogen (Px+Ovx+E), Px+Ovx receiving melatonin (Px+Ovx+M) and Px+Ovx estrogen and melatonin supplemented (Px+Ovx+EM) group (EM group). We evaluated reduced glutathione (GSH) levels and malondialdehyde (MDA) levels. The mean collagen fiber (CF)/smooth muscle (SM) ratio in the bladder wall and structure of the kidney were examined histolologically. We also recorded response of the bladder contractility to acetylcholine (Ach). RESULTS: Px and Ovx groups showed statistically significant reductions of antioxidant defenses, impaired Ach-evoked contraction, histological changes compared with the control group. Also, these changes were prominent in Px+Ovx group compared with all other groups. Both estrogen and melatonin reversed these changes however best restoration was observed in the EM group. CONCLUSIONS: Px performed in addition to Ovx led to a distinct increase in oxidative damage in bladder and renal tissue and deteriorate of the detrussor function. Either estradiol or melatonin replacement alone or in combination prevents significant alterations of tissue histology and bladder contractility following Ovx and Px. Thus, combination treatment appears to be the best method to restore both contractility and histomorphology of bladder and kidney tissues after Ovx and Px (Tab. 3, Fig. 4, Ref. 44).

Melatonin influences on steroidogenic gene expression in the ovary of pinealectomized rats.

OBJECTIVE: To analyze the expression of genes related to steroidogenesis in the ovary of pinealectomized rats. DESIGN: Experimental research. SETTING: University research laboratory. ANIMAL(S): Thirty female adult rats. INTERVENTION(S): Administration of vehicle (GI), pinealectomy with vehicle (GII), or pinealectomy with melatonin replacement (10 µg/night) for 60 consecutive days (GIII), then euthanasia after 2 months of treatment, ovary collection complementary DNA microarray analyses, confirmatory quantitative reverse-transcriptase polymerase chain reaction analyses, and immunohistochemical analyses for localizing steroidogenesis changes in the ovary. MAIN OUTCOME MEASURE(S): Biologic molecular study followed by immunohistochemical analysis. RESULT(S): The changes in the expression of CYP11A1, CYP17A1, and CYP19A1 after pinealectomy (GII) compared with control (GI) showed the Cyp17a1 expression level increased in the theca interna and interstitial cells in the GII rats compared with the other groups. CONCLUSION(S): Melatonin deprivation (pinealectomy) or administration may influence the ovarian CYP17A1 expression and steroidogenesis.

Gamma knife surgery for pineal region tumors: an alternative strategy for negative pathology / Cirurgia com gamma knife como tratamento experimental para tumores da região da pineal: uma estratégia alternativa quando os dados anatomopatológicos são negativos

Objective : Pineal region tumors (PRTs) are uncommon, and treatments vary among neoplasm types. The authors report their experience with gamma knife surgery (GKS) as an initial treatment in a series of PRT patients with unclear pathological diagnoses. Method : Seventeen PRT patients with negative pathology who underwent GKS were retrospectively studied. Nine patients had further whole-brain and spinal cord radiotherapy and chemotherapy 6–9 months after GKS. Results : Sixteen of 17 cases were followed up over a mean of 33.3 months. The total response rate was 75%, and the control rate was 81.3%. No obvious neurological deficits or complications were attributable to GKS. Conclusion : The findings indicate that GKS may be an alternative strategy in selected PRT patients who have negative pathological diagnoses, and that good outcomes and quality of life can be obtained with few complications. .

Tumores da região da pineal (TRP) são pouco frequentes e as propostas de tratamento são bastante variadas. Os autores relatam sua experiência em cirurgias com uso gamma knife (CGK) como tratamento experimental inicial em séries de TRP que não têm diagnóstico anatomopatológico ou nos quais o diagnóstico não ficou claro. Foram estudados retrospectivamente 17 pacientes com TRP nestas condições e que foram submetidos a CGK. Destes, 9 pacientes foram submetidos posteriormente a radioterapia de todo o encéfalo e medula espinhal entre 6 e 9 meses depois da CGK. Dezesseis dos 17 pacientes foram acompanhados por um período médio de 33,3 meses. A taxa total de resposta nos pacientes foi de 75% e a taxa dos controles, 81,3%. Não houve nenhum déficit neurológico evidente que pudesse ser atribuído à CGK. A CGK como tratamento experimental pode ser uma estratégia alternativa no grupo específico de pacientes com TRP em que não há diagnóstico anatomopatológico, podendo ser obtida uma boa qualidade de vida com poucas complicações para esse grupo de pacientes.

Evaluation of the role of chronic daily melatonin administration and pinealectomy on penicillin-induced focal epileptiform activity and spectral analysis of ECoG in rats: an in vivo electrophysiological study.

In the present study, we aimed to investigate the effects of pinealectomy and chronic melatonin administration on focal epileptiform activity induced by penicillin in the rat cortex and to determine the relation between melatonin levels and electrocorticogram (ECoG) power spectrum. For this purpose, male Sprague-Dawley rats were divided into six groups: control, sham operated, ethanol, melatonin, pinealectomy and pinealectomy + melatonin group. Melatonin-treated rats was intraperitoneally injected with a daily single dose of 10 mg/kg melatonin for 14 days, but the last dose was given 30 min after local application of penicillin as a convulsant agent. Focal epileptiform activity was produced by intracortical administration of penicillin (200 units/1 µl). While chronic melatonin application did not affect either the onset latency or the spike frequency of epileptiform activity, pinealectomy significantly reduced latency to onset of initial epileptiform discharges and increased cortical epileptiform activity. However, acute melatonin administration decreased the epileptiform activity. The results also indicated that exogenously applied melatonin did not change the spectral analysis of ECoG, but pinealectomy led to a reduction in the power of the fast bands (gamma) power in ECoG. We conclude that endogenous melatonin signaling seem to have a tonic inhibitory action on neuronal excitability and epileptiform activity, and also a certain concentration of melatonin required for normal cortical excitability.

Effects of pinealectomy and melatonin supplementation on endometrial explants in a rat model.

OBJECTIVE: To determine the effects of pinealectomy on endometrial explants in rats and evaluate the activity of superoxide dismutase (SOD) and catalase (CAT) and the levels of malondialdehyde (MDA) in the rat endometriosis model. STUDY DESIGN: Rats with experimentally induced endometriosis were randomly divided into three groups after second-look laparotomies. Group 1 (pinealectomy, n = 8) and Group 2 (pinealectomy+melatonin, n = 8) underwent pinealectomies after the second-look laparotomies. Group 3 was presented as control group (vehicle solution+without pinealectomy (n = 6)). Melatonin was administered intraperitoneally for 4 weeks in Group 2, whereas an equal volume of vehicle solution was given to Groups 1 and 3. Evaluation of the volume of the endometrial explants, histopathological examination and preservation of explant epitheliums according to the scoring system were undertaken. RESULTS: There was a statistically significant increase in spherical explant volumes of Group 1 compared to Groups 2 and 3. In Group 1, the level of MDA was significantly higher and SOD and CAT activity was significantly lower compared to Groups 2 and 3. A statistically significant increase in the epithelial lining scores of explants was noted in Group 1 compared to Groups 2 and 3. CONCLUSION: The effects of pinealectomy on the progression of endometriosis explants were reversed by melatonin.

[Influence of peptides from pineal gland on thymus function at aging].

The interference between thymus and pineal gland during their involution is considered in this review. The research data about influence of thymus peptides on pineal gland and pineal peptides on thymus is summarized. Analysis of these data showed that pineal peptides (epithalamin, epitalon) had more effective geroprotective effect on thymus involution in comparison with geroprotective effect of thymic peptides (thymalin, thymogen) on involution of pineal gland. The key mechanisms of pineal peptides effect on thymus dystrophy is immunoendocrine cooperation, which is realized as transcription's activation of various proteins.

Melatonin promotes neurogenesis in dentate gyrus in the pinealectomized rat.

It was previously shown that pinealectomy causes delayed loss of pyramidal neurons in rat hippocampal layers CA1/3 and that this is reversed by melatonin supplementation. Here, we used immunohistologic detection of doublecortin, a protein expressed in newborn neurons, to determine if melatonin supplementation promotes neurogenesis after pinealectomy. It was found that melatonin supplementation significantly increased the number of doublecortin immunoreactive neurons in the dentate gyrus over the postsurgical intervals of 2, 4, 6, 8, 10 and 17 months. The increase was most evident at 6 months postsurgery and thereafter, and was apparent despite a severe decline in doublecortin-labeled cells over the 17 month postsurgical interval in all groups of rats. Doublecortin immunoreactive cells were not observed in the pyramidal layer itself. These results indicate that melatonin promotes neurogenesis in the dentate gyrus of pinealectomized rats. However, it is equivocal that these newborn neurons migrate to the pyramidal layer and account for the reappearance of neurons at this location in these rats. This study provides further evidence for a role of melatonin in promoting neurogenesis, adding another role to its already remarkably pleiotropic profile. The scope and significance of this newly discovered role remains to be determined.

[Acupuncture treatment for a patient with prolonged consciousness disturbance after a brain tumor surgery].

Acupuncture has long been applied as a therapeutic technique in China, Japan, Korea and other countries. Recently, its application began to be extended to the treatment of neural disorders. We experienced a 13-year-old boy with prolonged consciousness disturbance after a pineal tumor surgery and muscle contracture of lower extremity by long-term recumbency. We applied him acupuncture treatment for 4 months which was effective to alleviate these symptoms. Repeated IMP SPECT showed improvement of the cerebral blood flow (CBF) during the course of acupuncture therapy. Acupuncture was effective to improve prolonged coma after a brain surgery and also muscle contracture by long-lasting recumbency. CBF showed a slight increase along with the recovery of consciousness suggesting a strong relevance between CBF and improvement of these symptoms.

Effects of simulated hypo- and hyper-reproductive conditions on the characteristics of circadian rhythm in hypothalamic concentration of serotonin and dopamine and in plasma levels of thyroxine, triiodothyronine, and testosterone in Japanese quail, Coturnix coturnix japonica.

In this study, hypo- and hyper-reproductive conditions, as measured by concentrations of plasma testosterone in male Japanese quail held on long days LD 16:8, were experimentally simulated with injections of 5-hydroxytryptophan (5-HTP) and L-dihydroxyphenylalanine, (L-DOPA) with 8 h and 12 h phase angle differences between them in intact and melatonin-treated birds. The effects of these treatments were assessed on the characteristics of the circadian rhythm in the hypothalamic concentration of serotonin (5-HT), dopamine (DA), and plasma levels of thyroxine (T(4)), triiodothyronine (T(3))(,) and testosterone (T). These rhythms were also studied in sham-operated (SO), pinealectomized (Px), vehicle- (Veh), and melatonin (Mel)-treated birds. On the basis of the circadian mesors of the testosterone rhythms, three distinct categories could be identified: category A (i.e., normal breeding concentrations of plasma testosterone), which includes control, sham-operated, and vehicle-treated groups; category A(+) (i.e., concentrations of plasma testosterone higher than that found in normal breeding quail), which includes 12 h, 12 h+vehicle-treated, and Px quails; and category A(-) (concentrations of plasma testosterone lower than that found in normal breeding quail), which includes 8 h, melatonin-, and 12 h+melatonin-treated groups. It is evident that in normal and hypergonadal conditions (i.e., birds belonging to categories A and A(+)) the circadian rhythm in hypothalamic serotonin maintained a positive phase angle of about 16 h. In contrast, birds of category A(-) (i.e., in a hypogonadal condition) exhibited a negative phase angle of about 2 h. The present results clearly suggest that the internal phase relationship between the circadian rhythms in hypothalamic serotonin and dopamine might play a crucial role in strategizing and conferring a particular reproductive status to the birds. The role of circadian mechanisms involving circulating thyroid hormones in conferring reproductive status is completely ruled out, as no definite internal phase angle between these two hormonal rhythms was witnessed vis-a-vis different treatment groups. The testosterone peaks always occurred at the same time irrespective of breeding status of the bird, but with significant variation in its amplitude (high in hypergonadal and low in hypogonadal condition). It is suggested that administration of 5-HTP and L-DOPA at specific time interval and variation in pineal functions that modulate reproductive responses also alter the circadian pattern (acrophase and amplitude) of hypothalamic serotonin and dopamine, maintaining a specific phase relation between these cycles and breeding status. These findings strengthen our previous reports that a specific circadian phase relation of serotonergic and dopaminergic oscillations regulates reproduction. The present study strongly supports interdependence and specific relation of the two systems (gonadal activity and circadian pattern/phase relation of neural oscillation) in both natural and experimentally simulated conditions.

Melatonin treatment decreases c-fos expression in a headache model induced by capsaicin.

The aim of the present work was to analyze c-fos response within the trigeminal nucleus caudalis (TNC) of pinealectomized rats and animals that received intraperitoneal melatonin, after intracisternal infusion of capsaicin, used to induce intracranial trigeminovascular stimulation. Experimental groups consisted of animals that received vehicle solution (saline-ethanol-Tween 80, 8:1:1, diluted 1:50) only (VEI, n=5); animals that received capsaicin solution (200 nM) only (CAP, n=6); animals submitted to pinealectomy (PX, n=5); sham-operated animals (SH, n=5); animals submitted to pinealectomy followed by capsaicin stimulation (200 nM) after 15 days (PX + CAP, n=7); and animals that received capsaicin solution (200 nM) and intraperitoneal melatonin (10 mg/kg) (CAP + MEL, n=5). Control rats, receiving vehicle in the cisterna magna, showed a small number of c-fos-positive cells in the TNC (layer I/II) as well as the sham-operated and pinealectomized rats, when compared to animals stimulated by capsaicin. On the other hand, pinealectomized rats, which received capsaicin, presented the highest number of c-fos-positive cells. Animals receiving capsaicin and melatonin treatment had similar expression of the vehicle group. Our data provide experimental evidence to support the role of melatonin and pineal gland in the pathophysiology of neurovascular headaches.

The effect of pinealectomy on plasma vasopressin response to isotonic, hypertonic and hypovolemic treatments in rats supplemented with L-thyroxine.

The present study was conducted to determine the effects of basal, isotonic as well as hypertonic and hypovolemic treatments on fluid-electrolyte balance and plasma AVP levels in rats supplemented with L-thyroxine and pinealectomized L-thyroxine. The animals were initially separated into 4 groups: control (n = 24), L-thyroxine treated (n = 24); L-thyroxine + sham-pinealectomy (n = 24) treated and 4-L-thyroxine + pinealectomy (n = 24) treated. L-thyroxine was given for 4 weeks. At the end of the 4-week experimental period, the sub-groups were formed before decapitation, which were classified as unstimulated (n = 6), isotonic (n = 6), hypertonic (n = 6) and hypovolemic (n = 6) stimulation. Plasma AVP, total triiodothyronine (TT3) and total thyroxine (TT4) levels were examined in plasma by RIA. Hematocrit and osmolality levels were also determined. It was found that the TT3 and TT4 levels showed significant increases in L-thyroxine treated groups (P <0.001). Also, plasma AVP levels increased in the group subjected to L-thyroxine treatment. However, this increase was depicted to be significantly more prominent in L-thyroxine + pinealectomy treated group (P <0.001). The results of the present study indicate that L-thyroxine treatment increases the basal and stimulated AVP release, which became more significant in the pinealectomy plus L-thyroxine treatment group. Moreover, the results indicate that AVP response to hypertonic and hypovolemic stimulations does not undergo any change due to supplementation by L-thyroxine treatment and/or pinealectomy plus L-thyroxine.

Melatonin stimulates the release of growth hormone and prolactin by a possible induction of the expression of frog growth hormone-releasing peptide and its related peptide-2 in the amphibian hypothalamus.

We recently identified a novel hypothalamic neuropeptide stimulating GH release in bullfrogs and termed it frog GH-releasing peptide (fGRP). The fGRP precursor encodes fGRP and its related peptides (fGRP-RP-1, -RP-2, and -RP-3), and fGRP-RP-2 also stimulates GH and prolactin (PRL) release. Cell bodies and terminals containing these neuropeptides are localized in the suprachiasmatic nucleus (SCN) and median eminence, respectively. To understand the physiological role of fGRP and fGRP-RP-2, we investigated the mechanisms that regulate the expression of these neuropeptides. This study shows that melatonin induces the expression of fGRP and fGRP-RPs in bullfrogs. Orbital enucleation combined with pinealectomy (Ex plus Px) decreased the expression of fGRP precursor mRNA and content of mature fGRP and fGRP-RPs in the diencephalon including the SCN and median eminence. Conversely, melatonin administration to Ex plus Px bullfrogs increased dose-dependently their expressions. The expression of fGRP precursor mRNA was photoperiodically controlled and increased under short-day photoperiods, when the nocturnal duration of melatonin secretion increases. To clarify the mode of melatonin action on the induction of fGRP and fGRP-RPs, we further demonstrated the expression of Mel(1b), a melatonin receptor subtype, in SCN neurons expressing fGRP precursor mRNA. Finally, we investigated circulating GH and PRL levels after melatonin manipulation because fGRP and fGRP-RP-2 stimulate the release of GH and GH/PRL, respectively. Ex plus Px decreased plasma GH and PRL concentrations, whereas melatonin administration increased these hormone levels. These results suggest that melatonin induces the expression of fGRP and fGRP-RP-2, thus stimulating the release of GH and PRL in bullfrogs.

Effect of melatonin and zinc on the immune response in experimental Toxoplasma retinochoroiditis.

OBJECTIVES: To investigate the possible effect of melatonin (MEL) and zinc on the immune response to Toxoplasma gondii retinochoroiditis in the rat model of infection and to establish the possible value of artificial MEL and/or zinc supplementation as adjunctive therapeutic agents in the treatment of T. gondii retinochoroiditis. METHODS: Eighty-four Sprague-Dawley male rats were divided into 12 equal groups. All groups, except controls were infected with T. gondii parasite by intraperitoneal injection. Combinations of zinc-deficient diet, pinealectomy (Px), and artificial zinc and MEL were supplied during a 1-month period. At the end of the experiment, retinal and choroidal total lymphocytes, CD3+, CD4+, and CD8+ cell numbers were counted in histological sections. RESULTS: The highest amount of cellular infiltration (lymphocytes, CD3+, CD4+, CD8+ cells) in the choroid and retina was detected in infected + MEL + zinc-treated rats, and the least amount of cellular infiltration was observed in Px + zinc-deficient diet-treated rats. Although single zinc or MEL supplementation had no significant impact on the cellular infiltration in the retina and choroid in Px rats, combined therapy significantly improved these responses. CONCLUSION: Artificial supplementation of MEL and zinc should be considered as an adjunctive therapy to classic treatment of Toxoplasma retinochoroiditis especially in immunosuppressed and elderly patients if our data are confirmed in a clinical setting.