D.P. Cardinali

Possible therapeutic value of melatonin in mild cognitive impairment : a retrospective study

Abstract:  Mild cognitive impairment (MCI) is an etiologically heterogeneous syndrome characterized by cognitive impairment preceding dementia. Approximately 12% of MCI patients convert to Alzheimer’s disease (AD) or other dementia disorders every year. In the present report we retrospectively examined the initial and final neuropsychological assessment of 50 MCI outpatients, 25 of whom had received daily 3–9 mg of a fast‐release melatonin preparation p.o. at bedtime for 9–18 months. Melatonin was given in addition to the standard medication prescribed by the attending psychiatrist. Patients treated with melatonin showed significantly better performance in Mini Mental State Examination and the cognitive subscale of the Alzheimer’s Disease Assessment Scale. After application of a battery of neuropsychological tests including Mattis’ test, Digit‐symbol test, Trail A and B tasks and the Rey’s verbal test, better performance was found in melatonin‐treated patients, except for the Digit‐symbol test score which remained unchanged. Abnormally high Beck Depression Inventory scores decreased in melatonin‐treated patients, concomitantly with an improvement in wakefulness and sleep quality. The results suggest that melatonin can be a useful add‐on drug for treating MCI in a clinical setting.

Effect of Melatonin in Selected Populations of Sleep-Disturbed Patients

In an open pilot study on the efficacy of melatonin in the treatment of sleep disorders, patients with sleep disturbances alone, patients with sleep disturbances and signs of depression and patients with sleep disorders and dementia received 3 mg melatonin p.o. for 21 days, at bed time. After 2–3 days of treatment, melatonin significantly augmented sleep quality and decreased the number of awakening episodes in patients with sleep disturbances associated or not with depression. Estimates of next-day alertness improved significantly only in patients with primary insomnia. Agitated behavior at night (sundowning) decreased significantly in dementia patients. In a second retrospective study, 14 Alzheimer’s disease (AD) patients received 9 mg melatonin daily for 22–35 months. A significant improvement of sleep quality was found, while there were no significant differences between initial and final neuropsychological evaluation (Functional Assessment Tool for AD, Mini-Mental). The results indicate that melatonin can be useful to treat sleep disturbances in elderly insomniacs and AD patients.

Effect of Superior Cervical Ganglionectomy on 24-h Variations in Hormone Secretion from the Anterior Hypophysis and in Hypothalamic Monoamine Turnover During the Preclinical Phase of Freund's Adjuvant Arthritis in Rats

The effect of superior cervical ganglionectomy (SCGx) on 24‐h rhythms of circulating adrenocorticotropic hormone (ACTH), growth hormone (GH), prolactin and luteinizing hormone (LH) and of hypothalamic noradrenaline content and dopamine and serotonin turnover, was assessed in rats 3 days after administering Freunds complete adjuvant. In sham‐operated rats, Freunds adjuvant injection increased serum ACTH without affecting its diurnal rhythmicity. SCGx, performed 10 days earlier, suppressed 24‐h rhythmicity and augmented mean values of circulating ACTH. A depressive effect of immunization on GH release was found in both sham‐operated and SCGx rats. GH concentrations did not exhibit diurnal rhythmicity and decreased after immunization. Time‐of‐day‐related changes in serum prolactin were significant for all examined groups, except for SCGx‐immunized rats. Freunds adjuvant administration augmented prolactin secretion. Daily changes in serum LH concentration and a decrease after immunization were found in both sham‐operated and SCGx rats. SCGx: (i) counteracted inhibition of daily variations of noradrenaline content in medial hypothalamus of Freunds adjuvant‐injected rats; (ii) decreased anterior hypothalamic dopamine turnover and augmented it in the medial hypothalamus; (iii) lowered amplitude of serotonin turnover rhythm in medial hypothalamus. The data indicate that several early changes in levels and 24‐h rhythms of circulating ACTH and prolactin, and in hypothalamic noradrenaline content and dopamine and serotonin turnover, were modified by a previous SCGx in Freunds adjuvant‐injected rats.

Experimental allergic encephalomyelitis in male Lewis rats subjected to calorie restriction

This work analyzes the effect of calorie restriction on the development of experimental allergic encephalomyelitis (EAE) in Lewis rats. Plasma levels of ACTH, corticosterone, prolactin and growth hormone (GH) and mitogenic responses in submaxillary lymph nodes were measured. Male Lewis rats (6 weeks-old) were submitted to a calorie restriction equivalent to 66% of food restriction or to a normal diet. Fifteen days later, rats were injected with complete Freund’s adjuvant plus spinal chord homogenate (SCH) or with complete Freund’s adjuvant alone. Rats were monitored daily for clinical signs of EAE and were killed on day 15 after immunization. Only rats subjected to normal diet exhibited clinical signs of the disease. The increase in plasma ACTH and corticosterone found after SCH immunization in controls was not detectable in calorie restricted rats. Likewise, the correlation between circulating ACTH and corticosterone was no longer found after calorie restriction. Generally, calorie restriction by itself augmented plasma ACTH or corticosterone and this increase was not further amplified by SCH immunization. Only calorie restricted rats exhibited augmented plasma prolactin levels after SCH immunization, and decreased plasma GH levels regardless of immunization. Calorie restriction depressed the mitogenic response of lymphoid cells to concanavalin A but not to lipopolysaccharide. Calorie restricted rats did not exhibit augmented mitogenic response to concanavalin A following SCH immunization as those found in controls. The results are compatible with the view that the course of EAE can be significantly modified by caloric restriction.ResumenEn este trabajo se analiza el efecto de la restricción calórica en el desarrollo de encefalitis alérgica experimental (EAE) en ratas de la cepa Lewis. Se evaluaron los niveles plasmáticos de ACTH, corticosterona, prolactina y hormona de crecimiento, y las respuestas mitogénicas en ganglios linfáticos submaxilares. Se utilizaron ratas macho de 6 semanas de vida sometidas a restricción calórica del 66% o a dieta normal. Tras 15 días, se les inyectó adyuvante completo de Freund emulsionado con homogenado de médula espinal (HME) o sólo el adyuvante. Se evaluaron diariamente los signos clínicos de EAE, sacrificándose las ratas a los 15 días de la inmunización. Sólo los animales mantenidos con dieta normal mostraron signos clínicos de la enfermedad. Las ratas con dieta restringida no exhibieron los aumentos significativos en ACTH y corticosterona detectados en ratas inmunizadas con HME, ni tampoco se obtuvo la correlación significativa entre los niveles circulantes de ACTH y corticosterona observada en los animales sometidos a dieta normal. De forma general, la restricción calórica aumentó los niveles de ACTH y corticosterona y este aumento no se afectó por la inmunización con HME. Sólo en las ratas sometidas a restricción calórica se obtuvo aumento en la secreción de prolactina tras la inmunización con HME. Los niveles de hormona de crecimiento disminuyeron en los animales con dieta restringida. La restricción calórica redujo la respuesta mitogénica de los ganglios linfáticos ante la concana-valina A, pero no ante el lipopolisacárido. La inmunización con HME provocó un aumento de la respuesta mitogénica ante concanavalina A sólo en ratas con dieta normal. Estos resultados indican que la restricción calórica puede afectar significativamente la evolución de la encefalitis alérgica experimental.

Aging-induced changes in 24-h rhythms of mitogenic responses, lymphocyte subset populations and neurotransmitter and amino acid content in rat submaxillary lymph nodes during Freund's adjuvant arthritis.

In young (two months) and aged (18 months) male rats injected s.c. with Freunds adjuvant or adjuvants vehicle 18 days earlier, 24-h variations in mitogenic responses, lymphocyte subsets and monoamine and amino acid content were examined in submaxillary lymph nodes. Mitogenic responses to concanavalin A (Con A) and lipopolysaccharide (LPS) were higher during the light phase of daily photoperiod. Old rats exhibited a suppressed or impaired mitogenic response to Con A but not to LPS. Acrophases of 24-h rhythm in lymphocyte subset populations in submaxillary lymph nodes were: 18:37-19:44h (B cells), 09:00-10:08h (T and CD4(+) cells) and 12:19-15:58h (CD8(+) cells). Aging augmented B cells and decreased T, CD4(+) and CD8(+) cells. Significant correlations were found between Con A activity and T cells, between lymph node 5HT content and B, T and CD8(+) lymphocytes, and between lymph node 5HT and taurine and GABA content. Aging increased lymph node 5HT content but did not modify NE content. Lymph node concentration of aspartate, glutamate and taurine was higher at night while that of GABA attained peak values at late afternoon. Old rats injected with Freunds adjuvant showed a higher mean value (glutamate) and smaller amplitude (glutamate, taurine) than their respective young controls. The results further document the effects of aging on the chronobiology of the immune system.

Melatonin as a Time-Meaningful Signal in Circadian Organization of Immune Response

Melatonin is synthesized and secreted during the dark period of the light/dark cycle. The rhythmic nocturnal melatonin secretion is directly generated by the circadian clock, located within the suprachiasmatic nuclei in mammals and is entrained to a 24-hour period by the light-dark cycle. The periodic secretion of melatonin may be used as a circadian mediator to any system that can ‘read’ the message. Melatonin seems to act as an arm of the circadian clock, giving a time-related signal to a number of body functions; one of these, the circadian organization of the defense of the organism, is discussed in some detail as an example.

Cerebroventricular Administration of Interferon-Gamma Modifies Locomotor Activity in the Golden Hamster

The present study was undertaken to examine whether the intracerebroventricular (i.c.v.) administration of interferon (IFN)-gamma could modify 24-hour wheel running locomotor activity in the golden hamster. Hamsters implanted with a cannula in the third ventricle received a single i.c.v. injection of 1 µl of murine recombinant IFN-gamma (40 IU/µl) or its vehicle (saline) at ZT 6 or ZT 18 (with ZT 12 defined arbitrarily as the time of lights off) and their activities were monitored during 24 h. The i.c.v. administration of IFN-gamma at ZT 6 produced a significant phase advance in acrophase of rhythm, an effect not seen at ZT 18. Also, IFN-gamma depressed mesor value significantly, the effect was seen at both times. These results clearly showed that the circadian clock could be modified by IFN-gamma microinjections. One explanation could be the presence of IFN-gamma receptor in the rat suprachiasmatic nucleus, supporting a direct effect on the central oscillator. However, another hypothesis could not be ruled out.

Changes of prolactin regulatory mechanisms in aging: 24-h rhythms of serum prolactin and median eminence and adenohypophysial concentration of dopamine, serotonin, (γ-aminobutyric acid, taurine and somatostatin in young and aged rats

Twenty-four hour rhythmicity of serum prolactin and median eminence and anterior pituitary content of dopamine (DA), serotonin (5HT), gamma-aminobutyric acid (GABA), taurine and somatostatin were examined in 2 months-old and 18-20 months-old Wistar male rats. The concentration of prolactin was higher in aged rats, with peaks in both groups of rats at the early phase of the activity span. Median eminence DA content of young rats attained its maximum at the middle of rest span and decreased as prolactin levels augmented while the lowest values of adenohypophysial DA were observed at the time of prolactin peak. DA rhythmicity disappeared in aged rats. GABA content of median eminence and adenohypophysis was lower in aged rats, with maximal values of median eminence GABA at light-dark transition in young rats and at the second half of activity span in aged rats. Serum prolactin correlated positively with median eminence GABA in young rats and negatively with pituitary GABA in young and aged rats. Median eminence somatostatin peaked at the beginning of the activity phase (young rats) or at the end of the rest phase (aged rats). Prolactin levels and somatostatin content correlated significantly in young rats only. Median eminence and pituitary 5HT and taurine content did not change with age. The results indicate disruption of prolactin regulatory mechanisms with aging in rats.

Acute and Chronic Effects of Superior Cervical Ganglionectomy on in vitro Mitogenic Responses of Lymphocytes from Submaxillary Lymph Nodes of Pituitary-Grafted Rats

Male rats were grafted an anterior pituitary within breast muscles or received a sham operation on day 5 of life. At the 60th day of life, the sympathetic denervation of rat submaxillary lymph nodes was achieved by a bilateral sympathetic superior cervical ganglionectomy (SCGx; at 15.00 h). Rats were killed either 18 h later (acute SCGx) or after 12 days (chronic SCGx) to measure lipopolysaccharide (LPS)- and concanavalin A (ConA)-induced cell proliferation in submaxillary lymph nodes, submaxillary lymph node cellularity and serum prolactin levels. In control rats, acute SCGx significantly augmented LPS or ConA activity on lymph cells while chronic SCGx had no effect. In pituitary-grafted rats, acute SCGx depressed the mitogenic effect of LPS or ConA whereas chronic SCGx augmented it. A global inhibitory effect of surgical stress on submaxillary lymph node cellularity was found in rats subjected to SCGx or its sham operation 18 h earlier. Serum prolactin levels increased significantly in pituitary-grafted rats, particularly in those subjected to chronic SCGx. In pituitary-grafted rats, a significant effect of acute SCGx was apparent, with serum prolactin levels augmenting about twice in sham-SCGx rats, and to a significantly less extent in acute SCGx rats. The results provide further evidence of the immunomodulatory role of local sympathetic nerves in submaxillary lymph nodes.

Comparative effects of melatonin and vitamin E in restoring aortic relaxation in pancreatectomized rats

In a previous study we reported the efficacy of melatonin to restore the decreased relaxation response to acetylcholine (ACh) or to sodium nitroprusside (SNP) in aortic rings of rats turned hyperglycemic by subtotal pancreatectomy. The effect was amplified by pre-incubation in a high (44 mmol/l) glucose solution, a situation that resulted in oxidative stress. We hereby compare the effect of another antioxidant, vitamin E, with that of melatonin on ACh response in intact aortic rings or on SNP response in endothelium-denuded aortic rings obtained from pancreatectomized or sham-operated rats. Dose-response curves to ACh or SNP were performed in the presence or absence of melatonin or vitamin E (10-5 mol/l) in 10 or 44 mmol/l glucose medium. Melatonin was more effective than vitamin E in restoring Ach- or SNP-induced relaxation of aortic rings in a high glucose medium. The differences between the two antioxidants may rely on the ability of melatonin to diffuse readily into intracellular compartments.ResumenEn un estudio previo se describe la eficacia de la melatonina para restablecer la respuesta disminuida a la acetilcolina (ACh) o al nitroprusiato de sodio (SNP) de anillos aórticos de rata con pancreatectomía subtotal. Este efecto fue mayor en el grupo de anillos preincubados en solución de Krebs con elevada concentración de glucosa (44 mmol/l), lo que favorece la producción de estrés oxidativo. En el presente trabajo se comparan los efectos de la vitamina E y la melatonina sobre la respuesta a la ACh y al SNP de anillos aórticos con endotelio intacto o denudado, obtenidos a partir de ratas con pancreatectomía subtotal o con operación simulada (controles). Se realizaron curvas dosis-respuesta a la ACh o al SNP en medios de incubación con glucosa normal o alta con melatonina o vitamina E (10−5 mol/l). La melatonina fue más efectiva que la vitamina E para restablecer la relajación provocada por ACh o SNP en anillos aórticos expuestos a un medio con elevada concentración de glucosa. La diferencia entre el efecto de ambas sustancias antioxidantes podría deberse a la capacidad de la melatonina para difundir hacia el compartimiento intracelular.