Norio Okamoto

Daily rhythm of serum melatonin in patients with dementia of the degenerate type

The daily rhythm in serum melatonin levels was measured in patients with dementia of the degenerate type (Alzheimers disease, Picks disease and senile dementia of the Alzheimer type) by radioimmunoassay. Thirteen patients (age: 69.0 +/- 8.0 years, mean +/- S.D.) were studied. All patients were hospitalized at the time of the study and had a history of sleep-wake disturbances, nocturnal wandering and/or delirium. We also studied 13 age-matched healthy control subjects (control group 1), ten young adults (control group 2), and nine hospitalized patients without dementia (control group 3). Two subjects in the control groups showed no measurable changes in melatonin level throughout the day, while the other 30 control subjects exhibited a clear daily rhythm with the peak concentration occurring during the night. On the other hand, four out of the 13 patients with dementia did not show any melatonin rhythm. Two of the demented patients who did not exhibit melatonin rhythm displayed clinical symptoms of rhythm disorders. One out of the nine patients with melatonin rhythm presented with clinical symptoms, such as delirium and sleep-wake disturbance. Our results suggest that the probability of absent melatonin rhythm is higher in demented patients compared with subjects without dementia. However, a lack of melatonin rhythm is not always associated with symptomatic rhythm disorders. Since the melatonin rhythm reflects that of the suprachiasmatic nucleus, it follows that the SCN function of the patients having a history of rhythm disorders was not always severely damaged.

Daily rhythm of serum melatonin levels and effect of light exposure in patients with dementia of the Alzheimer’s type

BACKGROUND Several studies have suggested that patients with dementia experience a deterioration of biological rhythms. We investigated the daily profile of serum melatonin levels in patients with dementia of the Alzheimers type (AD), since daily melatonin rhythm is thought to reflect the functioning of the biological clock. METHODS Seventeen inpatients with AD, 10 psychiatric inpatients without dementia, and 11 elderly healthy volunteers participated in this study. Serum melatonin was assessed every 3 hours by radioimmunoassay. RESULTS A daily fluctuation of melatonin levels with a significant nocturnal increase was observed in all three subject groups. However, both the AD patients and psychiatric patients without dementia showed significantly higher levels of melatonin in the daytime compared with the healthy subjects. When the effect of bright light exposure on melatonin secretion was investigated in six AD patients and five psychiatric patients without dementia, the daytime levels were markedly decreased in the patients without dementia, while no change was observed in the AD patients. CONCLUSIONS The high levels of melatonin in the daytime associated with a lack of response to light exposure in AD patients may be due to the neurodegenerative process of this disease.

Melatonin Receptors in the Spinal Cord

The pineal hormone, melatonin, plays an important role in the regulation of diurnal and seasonal rhythms in animals. In addition to the well established actions on the brain, the possibility of a direct melatonin action on the spinal cord has to be considered. In our laboratory, we have obtained data suggesting that melatonin receptors are present in the spinal cords of birds and mammals. Using radioreceptor binding and quantitative autoradiography assays with 2-[125I]iodomelatonin as the specific melatonin agonist, melatonin binding sites have been demonstrated in the rabbit and chicken spinal cords. These sites are saturable, reversible, specific, guanosine nucleotide-sensitive, of picomolar affinity and femtomolar density. The linearity of Scatchard plots of saturation data and the unity of Hill coefficients indicate that a single class of melatonin binding sites is present in the spinal cord membranes studied. The picomolar affinity of these sites is in line with the circulating levels of melatonin in these animals suggesting that these sites are physiologically relevant. Autoradiography studies in the rabbit spinal cord show that melatonin binding sites are localized in the central gray substance (lamina X). In the chicken spinal cord, these binding sites are localized in dorsal gray horns (laminae I-V) and lamina X. As lamina X and laminae I-II have similar functions, melatonin may have comparable roles in the chicken and rabbit spinal cords. Moreover, in the chicken spinal cord, the density of 2-[125I]iodomelatonin binding in the lumbar segment was significantly higher than those of the cervical and thoracic segments. The densities of these binding sites changed with environmental manipulations. When chickens were adapted to a 12L/12D photoperiod and sacrificed at mid-light and mid-dark, there was a significant diurnal variation in the density (maximum number of binding sites; Bmax) of melatonin binding sites in the spinal cord. After constant light treatment or pinealectomy, the Bmax of melatonin receptors in the chicken spinal cord increased significantly in the subjective mid-dark period. Moreover, there was an age-related decrease in the 2-[125I]iodomelatonin binding to the chicken spinal cord. Our results suggest that melatonin receptors in the chicken spinal cord are regulated by environmental lighting and change with development. These receptors may play an important role in the chronobiology of spinal cord function. The biological responses of melatonin on spinal cords have also been demonstrated in vitro. Melatonin decreased the forskolin-stimulated cAMP production in the chicken spinal cord explant. Preincubation with pertussis toxin blocked the melatonin effect. Our results suggest that melatonin receptors in the chicken spinal cord are linked to the adenylate cyclase via a pertussis toxin-sensitive G protein and that melatonin binding sites in spinal cords are melatonin receptors with biological functions. These receptors may be involved in the regulation of spinal cord functions related to sensory transmission, visceral reflexes and autonomic activities.

Atypical depressive symptoms possibly predict responsiveness to phototherapy in seasonal affective disorder

Phototherapy was administered to 24 depressed patients with seasonal affective disorder (SAD), of which 62%, 24%, and 14%, respectively, showed improvements of greater than or equal to 50%, 25-50%, and less than 25% based on the Hamilton rating scale for depression for SAD (HAMSAD). No patients showed aggravation or side effects. Although the improvement rate in HAMSAD correlated significantly with the pretreatment severity of atypical symptoms of depression, it did not correlate with that of typical symptoms. This suggests that phototherapy is a useful treatment in SAD and that responsiveness to phototherapy in SAD can possibly be predicted by the atypical depressive symptoms before treatment.

Differential Pattern of the Circadian Rhythm of Serum Melatonin in Young and Elderly Healthy Subjects

The daily profile of serum level of melatonin was studied in 10 young and 13 elderly subjects. All of the subjects were physically and psychiatrically healthy and did not have any clinical symptoms related to rhythm disturbance. Blood samples were taken every 3 h for 1 day and serum melatonin levels were determined by RIA. All except for 1 of the elderly subjects exhibited a clear circadian rhythm of serum melatonin level with a nocturnal peak. In both subject groups, the melatonin rhythm showed significant diurnal variation. There was no significant difference in the total melatonin level per day between young and elderly groups, suggesting that there was no influence of aging on daily total melatonin secretion. However, there was a marked difference in the features of the melatonin rhythm between the two groups, i.e., a rapid decline of the melatonin level from the nocturnal peak in the elderly group, suggesting that the off-set time of melatonin secretion advances with aging. Our findings suggest that the pattern of melatonin rhythm alters significantly without clear clinical symptoms in the process of senescence.

Investigation of responders and non-responders to long-term donepezil treatment

Background:  Donepezil is effective in maintaining the cognitive function of patients with mild to moderate Alzheimers disease (AD). However, not all patients respond to donepezil. In the present study, we examined the clinical features of responders and non‐responders to long‐term donepezil treatment.

Melatonin Excretion Rhythms in the Cultured Pineal Organ of the Lamprey, Lampetra japonica

Pineal organ of the lamprey, Lampetra japonica, is essential to keep the circadian locomotor activity rhythm as previously reported. In this paper, we tried to show that an endogenous oscillator is located and is working in the pineal organ. When the pineal organs were excised and cultured in a plastic tube with M199 medium at 20 degrees C, melatonin secretion rhythms were clearly observed under both light-dark and continuous dark conditions. The circadian secretion of melatonin continued for more than five cycles under the continuous dark condition. This indicates that the pineal organ has an endogenous oscillator and that the melatonin secretion rhythm is controlled by this oscillator. These findings suggest the possibility that the locomotor activity rhythm of the lamprey is under the control of the oscillator in the pineal organ.

ORIGINAL ARTICLE: Investigation of responders and non‐responders to long‐term donepezil treatment

Background:  Donepezil is effective in maintaining the cognitive function of patients with mild to moderate Alzheimers disease (AD). However, not all patients respond to donepezil. In the present study, we examined the clinical features of responders and non‐responders to long‐term donepezil treatment.

Investigation of the short- and long-term effects of donepezil on cognitive function in Alzheimer's disease

Background:  Donepezil is effective in maintaining cognitive function in patients with mild to moderate Alzheimers disease (AD). However, not all patients respond to donepezil. In the present study, we examined the short‐ and long‐term effects of donepezil on cognitive function after 2 years treatment.

Transient fluctuation of serum melatonin rhythm is suppressed centrally by vitamin B12.

Vitamin B12 has been reported to improve sleep-wake rhythm disorders. Although the mechanism is still unclear, a change in the sensitivity of the circadian clock system to photic input is thought to be a possible mechanism of the effect. In this study, the effect of the vitamin B12 on the circadian aspect of the electroretinogram (ERG) and serum melatonin level was analyzed in rats. Vitamin B12, alpha-(5,6-dimethylbenzimidazolyl)-co-methyl-cobamide was daily administrated subcutaneously for 8 weeks to adult male Wister rats in the experimental group, and saline was given to the control group. The ERGs were recorded under dark adaptation during the night and day, and under light adaptation (0.1 lux) during the night. Blood was drawn before and after ERG recording. The amplitudes of the a-wave, b-wave, and trough-to-peak of both waves and latencies of ERG were analyzed following various exposures to stimuli of light intensity. These parameters in the group treated with vitamin B12 showed similar characteristics to the control group, and no significant difference was observed between the two groups. The melatonin levels of both groups before the measurement of ERG were similar under each measurement condition. The elevated serum melatonin concentration in the control group under dark adaptation at night was suppressed after the series of 10-msec light stimuli used for measurement of ERG. However, this suppressing effect of light pulses on melatonin level was significantly inhibited in the group treated with vitamin B12. Under light adaptation during the night and under dark adaptation during the day, melatonin levels after the measurement of ERG were not different between the groups. From these results, it is suggested that vitamin B12 if effective in suppressing melatonin rhythm disturbances introduced by transient light stimulation, and it affects the site more central than the retinal level.