sb-334867-a and Seizures

Convulsive seizures are due to abnormal synchronous and repetitive neuronal discharges in the central nervous system (CNS). Finding new therapeutics to overcome the side effects of the current drug therapies and to increase their effectiveness is ongoing. Orexin-A and orexin-B are brain neuropeptides originating from postero-lateral hypothalamic neurons. Studies show that orexins, through activation of OX1 and OX2 receptors, have excitatory effects in the CNS. Accordingly, this study was designed to evaluate the effect of OX1 receptor antagonist (SB-334867) on seizure- and anxiety-related behaviors of pentylenetetrazol (PTZ)-kindled rats. Kindling was induced by repeated intraperitoneal (IP) injections of PTZ (32 mg/kg) with two-day intervals for 24 days in male Wistar rats. Three groups received intracerebroventricular (ICV) injections of SB-334867 (2.5, 5, and 10 μg/rat) before PTZ injections. Two control groups received vehicle (2 μL/rat, ICV) and valproate (26 μg/rat, ICV) before PTZ injections. An extra group of control animals received saline both ICV and IP. Seizure-related behaviors were monitored for 30 min following PTZ administration. The anxiety-like behaviors were also assessed using elevated plus-maze in the first and last days of the study. The results revealed that ICV injection of SB-334867, mainly at the dose of 10 μg/rat, decreased the median of seizure stages, prolonged the latency and reduced the duration of different seizure stages, and reversed the PTZ-induced anxiety-like behaviors. Based on the presented results, it is suggested that pharmacological blockade of the OX1 receptor is a potential target in the treatment of seizure and concomitant anxiety disorders.

Topics: Animals; Anxiety; Benzoxazoles; Dose-Response Relationship, Drug; Kindling, Neurologic; Male; Maze Learning; Naphthyridines; Orexin Receptor Antagonists; Orexin Receptors; Orexins; Pentylenetetrazole; Rats; Rats, Wistar; Seizures; Urea

Orexins A and B are hypothalamic neuropeptides involved in a number of physiological and behavioral processes. They work via OX1 and OX2 receptors. Recent studies revealed that orexins may be implicated in seizure activity. Therefore, the present study was undertaken to evaluate the influence of SB 334867 (a selective OX1 receptor antagonist) and EMPA (a selective OX2 receptor antagonist) on the seizure thresholds in mice. We also aimed to determine the changes of orexin A level following different types of seizures.. The intravenous pentylenetetrazole (i.v. PTZ) seizure test, the maximal electroshock seizure threshold (MEST) test and the 6 Hz seizure test were used in the present study. Brain orexin A level was determined via enzyme-linked immunoassay (ELISA).. SB 334867 did not affect the seizure threshold for myoclonic twitches and tonic seizures in the i.v. PTZ seizure test. This compound, however, significantly raised the threshold for the PTZ-induced clonic seizures, for tonic hindlimb extension in the MEST test as well as for psychomotor seizures induced by 6 Hz stimulation. In comparison, EMPA did not alter the seizure thresholds in the i.v. PTZ test. Both EMPA and SB 334867 did not affect motor coordination and muscular strength. ELISA showed the increase of total brain orexin A level following different types of seizures.. Our results provide further evidence for the role of orexins in seizure activity and suggest that pharmacological blockade of the OX1 receptors may represent a novel therapeutic approach in the treatment of seizure disorders.

Topics: Animals; Anticonvulsants; Benzoxazoles; Brain Chemistry; Convulsants; Electroshock; Male; Mice; Muscle Strength; Myoclonus; Naphthyridines; Orexin Receptor Antagonists; Orexin Receptors; Orexins; Pentylenetetrazole; Psychomotor Performance; Seizures; Urea

Orexin has been shown to be involved in a number of physiological and behavioral processes including, feeding and metabolism, reward, nociception, and anxiety. Furthermore, orexin can cause increased neuronal excitability that gives rise to epileptic activity. The distribution of orexin receptor expression in the hippocampus, suggests a possible importance of orexin in the control of seizures in the temporal lobe epilepsy. Therefore, in this study, the effect of hippocampal orexin 1 and 2 receptors on seizure and glutamate and GABA (gamma-aminobutyric acid) contents was explored.. Orexin 1 receptor (OX1R) antagonist (SB) and OX2R antagonist (TCS) were administrated bilaterally through separate cannulae into both hippocampi. Behavioral convulsions were provoked by intravenous pentylenetetrazol (PTZ) application model. The amount of total hippocampal glutamate and GABA contents was then measured by a biochemical method.. SB (50 nmol) infusion reduced seizure stage, duration and decreased glutamate while GABA content was increased. SB (200 nmol) also reduced seizure stage, duration and glutamate content, without change of GABA content. TCS (20 nmol) infusion reduced seizure stage and duration without concomitant change in glutamate and GABA contents. Further, TCS (40 nmol) did neither affect the seizure nor the GABA, while decreased glutamate content. Co-administration of SB (50 nmol) with TCS (40 nmol) and also SB (200 nmol) with TCS (40 nmol) reduced seizure stage, duration and glutamate, but increased GABA content.. It is concluded that OX1R and OX2R antagonists reduce convulsive intensity, partially through alterations of hippocampal glutamate and GABA contents.

Topics: Animals; Benzoxazoles; Convulsants; gamma-Aminobutyric Acid; Glutamic Acid; Hippocampus; Isoquinolines; Male; Microinjections; Naphthyridines; Orexin Receptor Antagonists; Orexin Receptors; Pentylenetetrazole; Pyridines; Rats; Seizures; Urea

Sleep deprivation has been shown to be an activator of seizures in clinical and animal studies. Orexin-A was speculated to be involved in the aggravation of seizures by sleep deprivation through the activation of its receptors: orexin-1 and orexin-2 receptor (OX1R and OX2R, respectively). Therefore, we aimed to investigate the effects of pre-treating sleep-deprived Wistar rats with the OX1R or OX2R antagonists, SB334867 (30 nM/kg) or TCS OX2 29 (30 nM/kg), respectively, followed by a convulsive dose of 50 mg/kg pentylenetetrazol administration (seizure induction), on seizure behavior, and hippocampal neurodegeneration and cellular proliferation. Our results revealed that treatment with SB334867 or TCS OX2 29 significantly prolonged the latency and reduced the duration of seizures, while also lowering the mortality rate in sleep-deprived rats exposed to pentylenetetrazol. In addition, SB334867 or TCS OX2 29 reduced the damage to hippocampal CA3 neurons and the number of bromodeoxyuridine-positive cells in the dentate gyrus (particularly in the hilus). Overall, the effect of TCS OX2 29 was greater than that of SB334867. Taken together, these data suggest that OX1R and OX2R antagonists may alleviate the damage of pentylenetetrazol-induced seizures that are exacerbated by sleep deprivation, and furthermore could be associated with a reduction of neuronal damage in the hippocampus and the inhibition of cellular proliferation in the dentate gyrus.

Topics: Animals; Benzoxazoles; CA3 Region, Hippocampal; Cell Proliferation; Convulsants; Dentate Gyrus; Hippocampus; Intracellular Signaling Peptides and Proteins; Isoquinolines; Male; Naphthyridines; Neurons; Neuropeptides; Neuroprotective Agents; Orexin Receptor Antagonists; Orexin Receptors; Orexins; Pentylenetetrazole; Pyridines; Rats; Rats, Wistar; Seizures; Sleep Deprivation; Time Factors; Urea