Abnormal hippocampal melatoninergic system: a potential link between absence epilepsy and depression-like behavior in WAG/Rij rats?

Absence epilepsy and depression are comorbid disorders, but the molecular link between the two disorders is unknown. Here, we examined the role of the melatoninergic system in the pathophysiology of spike and wave discharges (SWDs) and depression-like behaviour in the Wistar Albino Glaxo from Rijswijk (WAG/Rij) rat model of absence epilepsy. In WAG/Rij rats, SWD incidence was higher during the dark period of the light-dark cycle, in agreement with previous findings. However, neither pinealectomy nor melatonin administration had any effect on SWD incidence, suggesting that the melatoninergic system was not involved in the pathophysiology of absence-like seizures. Endogenous melatonin levels were lower in the hippocampus of WAG/Rij rats as compared to non-epileptic control rats, and this was associated with higher levels of melatonin receptors in the hippocampus, but not in the thalamus. In line with the reduced melatonin levels, cell density was lower in the hippocampus ofWAG/Rij rats and was further reduced by pinealectomy. As expected, WAG/Rij rats showed an increased depression-like behaviour in the sucrose preference and forced swim tests, as compared to non-epileptic controls. Pinealectomy abolished the difference between the two strains of rats by enhancing depression-like behaviour in non-epileptic controls. Melatonin replacement displayed a significant antidepressant-like effect in bothWAG/Rij and control rats. These findings suggest that a defect of hippocampal melatoninergic system may be one of the mechanisms underlying the depression-like phenotype inWAG/Rij rats and that activation of melatonin receptors might represent a valuable strategy in the treatment of depression associated with absence epilepsy

The role of the melatoninergic system in epilepsy and comorbid psychiatric disorders

Abstract There is emerging evidence of the beneficial role of the melatonin system in a wide range of psychiatric and neurologic disorders, including anxiety, depression, and epilepsy. Although melatoninergic drugs have chronobiotic and antioxidant properties that positively influence circadian rhythm desynchronization and neuroprotection in neurodegenerative disorders, studies examining the use of melatonin for epilepsy's comorbid psychiatric and neurological symptomatology are still limited. Preclinical and clinical findings on the beneficial effects of the melatonin system on anxiety, depression, and epilepsy suggest that melatoninergic compounds might be effective in treating comorbid behavioral complications in epilepsy beyond regulation of a disturbed sleep-wake cycle

Melatonin limits paclitaxel-induced mitochondrial dysfunction in vitro and protects against paclitaxel-induced neuropathic pain in the rat

Acknowledgements Thank you to Professor Ahmet Hoke (Johns Hopkins, Baltimore, USA) for the gift of DRG cells; and to Professor Patrick M. Dougherty (MD Anderson Cancer Center, Texas, USA) for sharing his expertise in the rat model. Funding The study was funded by the Association of Anaesthetists of Great Britain and Ireland, the British Journal of Anaesthesia/Royal College of Anaesthetists and the Melville Trust.Peer reviewedPublisher PD

Adenosine A2A receptors: localization and function

Adenosine is an endogenous purine nucleoside present in all mammalian tissues, that originates from the breakdown of ATP. By binding to its four receptor subtypes (A1, A2A, A2B, and A3), adenosine regulates several important physiological functions at both the central and peripheral levels. Therefore, ligands for the different adenosine receptors are attracting increasing attention as new potential drugs to be used in the treatment of several diseases. This chapter is aimed at providing an overview of adenosine metabolism, adenosine receptors localization and their signal transduction pathways. Particular attention will be paid to the biochemistry and pharmacology of A2A receptors, since antagonists of these receptors have emerged as promising new drugs for the treatment of Parkinson's disease. The interactions of A2A receptors with other nonadenosinergic receptors, and the effects of the pharmacological manipulation of A2A receptors on different body organs will be discussed, together with the usefulness of A2A receptor antagonists for the treatment of Parkinson's disease and the potential adverse effects of these drugs

Impact of Melatonin Deficit on Emotional Status and Oxidative Stress-Induced Changes in Sphingomyelin and Cholesterol Level in Young Adult, Mature, and Aged Rats

The pineal gland regulates the aging process via the hormone melatonin. The present report aims to evaluate the effect of pinealectomy (pin) on behavioral and oxidative stress-induced alterations in cholesterol and sphingomyelin (SM) levels in young adult, mature and aging rats. Sham and pin rats aged 3, 14 and 18 months were tested in behavioral tests for motor activity, anxiety, and depression. The ELISA test explored oxidative stress parameters and SM in the hippocampus, while total cholesterol was measured in serum via a commercial autoanalyzer. Mature and aged sham rats showed low motor activity and increased anxiety compared to the youngest rats. Pinealectomy affected emotional responses, induced depressive-like behavior, and elevated cholesterol levels in the youngest rats. However, removal of the pineal gland enhanced oxidative stress by diminishing antioxidant capacity and increasing the MDA level, and decreased SM level in the hippocampus of 14-month-old rats. Our findings suggest that young adult rats are vulnerable to emotional disturbance and changes in cholesterol levels resulting from melatonin deficiency. In contrast, mature rats with pinealectomy are exposed to an oxidative stress-induced decrease in SM levels in the hippocampus

Significance of Antioxidants on Aging and Neurodegeneration

The hallmark of aging is an organism’s difficulty to maintain proper homeostasis, leading to a disrupted balance between the endogenous antioxidant system and the production of free radicals, a progressive inflammatory process, and increased susceptibility to (neurodegenerative diseases [...

Chronic agomelatine treatment suppresses the kainate-induced glial reaction during epileptogenesis in rats

Inflammatory signal molecules are suggested to be involved in the mechanism underlying comorbid depression in epilepsy. The aim of this study was to examine the effect of the novel antidepressant agomelatine (Ago), a po­tent melatonin MT1 and MT2 receptor agonist and serotonin 5HT2C receptor antagonist, on glial activity during kainate (KA)-induced epileptogenesis.Brain sections were immunostained with the microglial marker Iba-1 and two astrocyte-specific markers, GFAP and S100 beta, and the glial cell morphology in brain structures vulnerable to KA-induced neurotoxicity was de­scribed in the KA-treated groups and their matched controls, respectively.Both control and Ago-treated groups were characterized with ramified microglial cells with fine processes. After administration of KA, activated Iba-1-immunoreactive microglial cells in the dorsal and ventral hippocampus, dentate gyrus, as well as in the basolateral amygdala (BLA) and piriform cortex were increased in number and displayed enlarged round-shaped bodies and arborization. Chronic Ago treatment during epileptogenesis sig­nificantly diminished their number compared to that in the matched vehicle-treated epileptic group, specifical­ly in the CA1a, CA1b, CA1c and CA3c subfields of dorsal hippocampus, BLA and piriform cortex. Conversely, the KA-induced reactive astrogliosis was more restricted and both GFAP- and S100 beta-immunostained cells were observed mainly in the CA1 and CA3c fields of dorsal hippocampus and piriform cortex. The Ago treatment did not significantly reduce the number of immunopositive astrocytes in the CA2, CA3a, CA3b subfields of the dor­ sal and CA1, CA2, CA3 subfields of the ventral hippocampus, the dentate gyrus and the BLA. In addition, only a few immunostained ramified astrocytes were scattered in the ventral hippocampus of the KA-veh group, while the Ago-treated group showed a considerable increase of immunoreactive cells in this area compared to controls.The present results show that chronic Ago treatment during epileptogenesis prevents the KA-induced microglial activation and suppresses the neuronal cell death in the vulnerable limbic regions. It can provide effective ther­apy for brain disorders involving neuronal damage, neuroinflammation and oxidative stress such as epilepsy

Data for: Pharmacological characterization of the cannabinoid receptor 2 agonist, β-caryophyllene on seizure models in mice

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