Zahiruddin Othman

Agomelatine in Depressive Disorders: Its Novel Mechanisms of Action

Disruptions in sleep and sleep-wake cycle regulation have been identified as one of the main causes for the pathophysiology of depressive disorders. The search has been on for the identification of an ideal antidepressant that could improve both sleep disturbances and depressive symptomatology. Melatonin, the major hormone of the pineal gland, has been shown to improve sleep and is involved in the regulation of the sleep-wake cycle. Identification of high concentrations of MT1 and MT2 melatonergic receptors in the suprachiasmatic nucleus of the anterior hypothalamus, the structure concerned with regulation of circadian rhythms and sleep-wake cycles, has led to the development of melatonergic agonists with greater potency and longer durations of action. Agomelatine is one such melatonergic agonist that acts specifically on MT1/MT2 melatonergic receptors and at the same time exhibits 5-HT2C antagonism, a property that is utilized by current antidepressants that are in clinical use. Agomelatine has been shown to be effective in a number of animal models of depression. Clinical studies undertaken on patients with major depression, bipolar disorders, seasonal affective disorder, and generalized anxiety disorder have all shown that agomelatine is also very effective in ameliorating depressive symptoms and manifesting early onset of action with a good tolerability and safety profile. It improved sleep efficiency and also resynchronized the disrupted circadian rhythms. Hence, the melatonergic modulation by agomelatine is suggested as one of the mechanisms for its antidepressant effect. Agomelatines action on dendritic neurogenesis in animal models of depression is also identified as yet another action.

Improvement in immediate memory after 16 weeks of tualang honey (Agro Mas) supplement in healthy postmenopausal women.

Objective:The aim of this study was to evaluate the verbal learning and memory performance of postmenopausal women who received tualang honey (Agro Mas) in comparison with women receiving estrogen plus progestin therapy and untreated controls. Methods:A total of 102 postmenopausal women were recruited and randomly assigned to three groups: tualang honey (20 mg/d), estrogen plus progestin therapy (Femoston 1/5), and untreated control. Their verbal learning and memory performances were assessed using the Malay version of the Auditory Verbal Learning Test before and after 16 weeks of intervention. Data were analyzed using the repeated-measures analysis of variance, and a P value of less than 0.05 was considered significant. Results:There were significant differences in the mean scores of total learning as well as the mean scores of trials A1, A5, A6, and A7 between the three groups. There were also significant differences in the overall mean scores of total learning and trials A1 and A5 between both estrogen plus progestin therapy and tualang honey groups when compared with the untreated control group. However, significant differences in the mean score for trials A6 and A7 were only observed between the estrogen plus progestin therapy and untreated control groups. Conclusions:Postmenopausal women who received tualang honey showed improvement in their immediate memory but not in immediate memory after the interference and delayed recall. This is comparable with the improvement seen in women receiving estrogen plus progestin therapy.

Tualang honey supplement improves memory performance and hippocampal morphology in stressed ovariectomized rats

Recently, our research team has reported that Tualang honey was able to improve immediate memory in postmenopausal women comparable with that of estrogen progestin therapy. Therefore the aim of the present study was to examine the effects of Tualang honey supplement on hippocampal morphology and memory performance in ovariectomized (OVX) rats exposed to social instability stress. Female Sprague-Dawley rats were divided into six groups: (i) sham-operated controls, (ii) stressed sham-operated controls, (iii) OVX rats, (iv) stressed OVX rats, (v) stressed OVX rats treated with 17β-estradiol (E2), and (vi) stressed OVX rats treated with Tualang honey. These rats were subjected to social instability stress procedure followed by novel object recognition (NOR) test. Right brain hemispheres were subjected to Nissl staining. The number and arrangement of pyramidal neurons in regions of CA1, CA2, CA3 and the dentate gyrus (DG) were recorded. Two-way ANOVA analyses showed significant interactions between stress and OVX in both STM and LTM test as well as number of Nissl-positive cells in all hippocampal regions. Both E2 and Tualang honey treatments improved both short-term and long-term memory and enhanced the neuronal proliferation of hippocampal CA2, CA3 and DG regions compared to that of untreated stressed OVX rats.

Enhancement of BDNF concentration and restoration of the hypothalamic-pituitary-adrenal axis accompany reduced depressive-like behaviour in stressed ovariectomised rats treated with either Tualang honey or estrogen.

A possible interaction between glucocorticoids and estrogen-induced increases in brain-derived-neurotrophic factor (BDNF) expression in enhancing depressive-like behaviour has been documented. Here we evaluated the effects of Tualang honey, a phytoestrogen, and 17β-estradiol (E2) on the depressive-like behaviour, stress hormones, and BDNF concentration in stressed ovariectomised (OVX) rats. The animals were divided into six groups: (i) nonstressed sham-operated control, (ii) stressed sham-operated control, (iii) nonstressed OVX, (iv) stressed OVX, (v) stressed OVX treated with E2 (20 μg daily, sc), and (vi) stressed OVX treated with Tualang honey (0.2 g/kg body weight daily, orally). Two months after surgery, the animals were subjected to social instability stress procedure followed by forced swimming test. Struggling time, immobility time, and swimming time were scored. Serum adrenocorticotropic hormone (ACTH) and corticosterone levels, and the BDNF concentration were determined using commercially available ELISA kits. Stressed OVX rats displayed increased depressive-like behaviour with significantly increased serum ACTH and corticosterone levels, while the BDNF concentration was significantly decreased compared to other experimental groups. These changes were notably reversed by both E2 and Tualang honey. In conclusion, both Tualang honey and E2 mediate antidepressive-like effects in stressed OVX rats, possibly acting via restoration of hypothalamic-pituitary-adrenal axis and enhancement of the BDNF concentration.

Tualang Honey Supplementation Reduces Blood Oxidative Stress Levels/Activities in Postmenopausal Women

This study aimed to investigate the ability of Tualang honey (TH), a phytoestrogen, to reduce blood oxidative stress levels/activities in postmenopausal women and compared the effects with the standard estrogen progestin therapy (EPT). A total of 78 healthy postmenopausal women were randomly assigned to one of two groups; EPT group received Femoston conti 1/5 (1 mg 17β-estradiol and 5 mg dydrogesterone), and TH group, received 20 g of TH supplement daily for 16 weeks. The reduced glutathione to oxidized glutathione ratio (GSH : GSSG), plasma glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD), and 4-hydroxynonenal (4-HNE) levels/activities were measured at pre- and postinterventions using commercially available kits. The plasma GPx and CAT activities were notably increased, and plasma 4-HNE level was significantly decreased in postmenopausal women who received EPT and TH supplementation. TH supplementation for 16 weeks was able to reduce blood oxidative stress levels/activities of postmenopausal women comparable to those who received EPT. Thus, TH has a potential to be used as antioxidant therapy to combat oxidative stress-induced neurodegenerative diseases. This trial is registered with NCT01300676.

Quantification of physiological disparities and task performance in stress and control conditions

In mental stress studies, cerebral activation and autonomic nervous system are important distinctly. This study aims to analyze disparities associated with scalp potential, which may have impact on autonomic activation of heart during mental stress. Ten healthy subjects participated in this study that performed arithmetic tasks in stress and control environment. Task difficulty was calculated from their correct responses. During the experiment, electroencephalogram (EEG) and electrocardiogram (ECG) signals were recorded concurrently. Sympathetic innervation of heart was estimated from heart rate (HR), which is extracted from the ECG. The value of theta Fz/alpha Pz was measured from EEG scalp potential. The results show a significant surge in the value of theta Fz/alpha Pz in stress as compared to baseline (p<;0.013) and control (p<;0.042). The results also present tachycardia while in stress as compared to baseline (p<;0.05). Task difficulty in stress is also considerably higher than control environment (p<;0.003).

Tualang honey improves memory performance and decreases depressive-like behavior in rats exposed to loud noise stress

Recent evidence has exhibited dietary influence on the manifestation of different types of behavior induced by stressor tasks. The present study examined the effects of Tualang honey supplement administered with the goal of preventing or attenuating the occurrence of stress-related behaviors in male rats subjected to noise stress. Forty-eight adult male rats were randomly divided into the following four groups: i) nonstressed with vehicle, ii) nonstressed with Tualang honey, iii) stressed with vehicle, and iv) stressed with honey. The supplement was given once daily via oral gavage at 0.2 g/kg body weight. Two types of behavioral tests were performed, namely, the novel object recognition test to evaluate working memory and the forced swimming test to evaluate depressive-like behavior. Data were analyzed by a two-way analysis of variance (ANOVA) using IBM SPSS 18.0. It was observed that the rats subjected to noise stress expressed higher levels of depressive-like behavior and lower memory functions compared to the unexposed control rats. In addition, our results indicated that the supplementation regimen successfully counteracted the effects of noise stress. The forced swimming test indicated that climbing and swimming times were significantly increased and immobility times significantly decreased in honey-supplemented rats, thereby demonstrating an antidepressant-like effect. Furthermore, cognitive function was shown to be intensely affected by noise stress, but the effects were counteracted by the honey supplement. These findings suggest that subchronic exposure to noise stress induces depressive-like behavior and reduces cognitive functions, and that these effects can be attenuated by Tualang honey supplementation. This warrants further studies to examine the role of Tulang honey in mediating such effects.

Mood and memory function in ovariectomised rats exposed to social instability stress.

This study aims to compare the effects of social instability stress on memory and anxiety- and depressive-like behaviour between sham-operated controls and ovariectomised (OVX) rats. Forty adult female Sprague-Dawley rats (8 weeks old) were randomly divided into four groups, (n = 10 per group). These were non-stressed sham-operated control rats, stressed sham-operated control rats, non-stressed OVX rats, and stressed OVX rats. The rats were subjected to social instability stress procedure for 15 days. Novel object recognition, open field, and forced swim tests were conducted after the stress procedure. Serum estradiol, ACTH and corticosterone levels were measured using commercially available ELISA kits. Lower serum estradiol level and uterine weight with higher weight gain were observed in OVX rats compared to sham-operated controls. Serum ACTH, and corticosterone levels were higher in stressed compared to non-stressed groups. Memory deficit and anxiety- and depressive-like behaviour were significantly increased in stressed compared to non-stressed OVX rats but these changes were not seen in sham-operated controls. These results suggest that the high circulating corticosterone acts synergistically with low circulating estradiol to exert negative effects on mood and memory function.

Association of oxidative stress and memory performance in postmenopausal women receiving estrogen-progestin therapy.

ObjectiveThe aim of this study was to examine the association between changes in blood oxidative stress level/activity and changes in memory performance among postmenopausal women. MethodsThis study involved 39 postmenopausal women who received estrogen-progestin therapy (EPT) for 16 weeks. Verbal learning and memory performance were assessed using the Malay Version of Auditory Verbal Learning Test before and after 16 weeks of EPT. Oxidative stress levels/activities before and after 16 weeks of EPT were determined using commercially available kits. Data were analyzed using paired t test and r. P < 0.05 was considered significant. ResultsThe activities of glutathione peroxidase and catalase were considerably increased (P < 0.05), but the level of 4-hydroxynonenal was notably decreased (P < 0.05), after 16 weeks of EPT. There were positive correlations between changes in plasma superoxide dismutase and changes in trial A2 scores (r = 0.36, P < 0.05), and between changes in the ratio of blood reduced glutathione to oxidized glutathione and changes in trial A2 scores (r = 0.34, P < 0.05). ConclusionsSixteen weeks of EPT increase blood antioxidant capacity. However, most of the changes in oxidative stress level/activity are not significantly associated with changes in the memory performance of postmenopausal women.

Tualang Honey Attenuates Noise Stress-Induced Memory Deficits in Aged Rats

Ageing and stress exposure may lead to memory impairment while oxidative stress is thought to be one of the underlying mechanisms involved. This study aimed to investigate the potential protective effects of Tualang honey supplementation on memory performance in aged rats exposed to noise stress. Tualang honey supplementation was given orally, 200 mg/kg body weight for 28 days. Rats in the stress group were subjected to loud noise, 100 dB(A), 4 hours daily for 14 days. All rats were subjected to novel object recognition test for evaluation of memory performance. It was observed that the rats subjected to noise stress exhibited significantly lower memory performance and higher oxidative stress as evident by elevated malondialdehyde and protein carbonyl levels and reduction of antioxidant enzymes activities compared to the nonstressed rats. Tualang honey supplementation was able to improve memory performance, decrease oxidative stress levels, increase brain-derived neurotrophic factor (BDNF) concentration, decrease acetylcholinesterase activity, and enhance neuronal proliferation in the medial prefrontal cortex (mPFC) and hippocampus. In conclusion, Tualang honey protects against memory decline due to stress exposure and/or ageing via enhancement of mPFC and hippocampal morphology possibly secondary to reduction in brain oxidative stress and/or upregulation of BDNF concentration and cholinergic system.