Long-Term Treatment with Losartan Attenuates Seizure Activity and Neuronal Damage Without Affecting Behavioral Changes in a Model of Co-morbid Hypertension and Epilepsy.

Over the last 10 years, accumulated experimental and clinical evidence has supported the idea that AT1 receptor subtype is involved in epilepsy. Recently, we have shown that the selective AT1 receptor antagonist losartan attenuates epileptogenesis and exerts neuroprotection in the CA1 area of the hippocampus in epileptic Wistar rats. This study aimed to verify the efficacy of long-term treatment with losartan (10 mg/kg) after kainate-induced status epilepticus (SE) on seizure activity, behavioral and biochemical changes, and neuronal damage in a model of co-morbid hypertension and epilepsy. Spontaneous seizures were video- and EEG-monitored in spontaneously hypertensive rats (SHRs) for a 16-week period after SE. The behavior was analyzed by open field, elevated plus maze, sugar preference test, and forced swim test. The levels of serotonin in the hippocampus and neuronal loss were estimated by HPLC and hematoxylin and eosin staining, respectively. The AT1 receptor antagonism delayed the onset of seizures and alleviated their frequency and duration during and after discontinuation of treatment. Losartan showed neuroprotection mostly in the CA3 area of the hippocampus and the septo-temporal hilus of the dentate gyrus in SHRs. However, the AT1 receptor antagonist did not exert a substantial influence on concomitant with epilepsy behavioral changes and decreased 5-HT levels in the hippocampus. Our results suggest that the antihypertensive therapy with an AT1 receptor blocker might be effective against seizure activity and neuronal damage in a co-morbid hypertension and epilepsy.

Long-term intracerebroventricular infusion of angiotensin II after kainate-induced status epilepticus: Effects on epileptogenesis, brain damage, and diurnal behavioral changes.

Our previous studies revealed that Angiotensin (Ang) II has anticonvulsant effects in acute seizure models. However, data on its role in experimental models of epilepsy are missing. In the present study, we tested whether posttreatment with Ang II after kainate (KA)-induced status epilepticus (SE) can affect epileptogenesis, concomitant behavioral changes, and brain damage. The Wistar rats were intracerebroventricularly infused via osmotic mini-pumps with Ang II (1.52µg/µl/day for 28days) after SE. Spontaneous motor seizures (SMS) were video-recorded for up to three months. Locomotor activity, anxiety, and depression-like behavior were evaluated during the last week of drug infusion, while spatial memory was assessed during the 3rd month after SE. Angiotensin II decreased the latency for onset of the first SMS and increased the frequency of SMS two months after SE. The continuous peptide infusion exacerbated the KA-induced hyperactivity and caused depression-like behavior. The reduced anxiety of KA-treated rats was alleviated by Ang II exposure. The KA-induced deficit in the hippocampal-dependent spatial memory was not influenced by Ang II. However, Ang II partially prevented the neuronal damage in the hippocampus, specifically in the CA1 area. The role of AT1 and AT2 receptor activation in the effects of the octapeptide is discussed.

Antiepileptogenic and neuroprotective effects of losartan in kainate model of temporal lobe epilepsy.

Recently, we have shown that the blockade of AT1 receptor might be useful as an adjuvant treatment strategy for the prevention of oxidative stress and neurotoxicity caused by status epilepticus (SE) in rats. The purpose of the present study was to further assess the efficacy of long-term treatment with losartan (10mg/kg), the selective AT1 receptor antagonist, during kainate (KA)-induced epileptogenesis in Wistar rats. Losartan treatment started after onset of SE and continued for 4weeks. The rats were video- and EEG-recorded for 3months. Locomotor activity, anxiety and depressive-like behavior were evaluated 9weeks after SE, when all rats had developed chronic epileptic state. Neuronal damage in hippocampus was analyzed by hematoxylin while serotonin (5-HT) levels in hippocampus by HPLC. AT1 receptor antagonism increased the latent seizure-free period and decreased the frequency of spontaneous motor seizures. Losartan positively affected epilepsy-provoked behavioral changes, including impulsivity, low anxiety level and depression in a phase-dependent manner and restored the changes in diurnal fluctuation of motor activity. Losartan exerted neuroprotection selectively in the CA1 area of the hippocampus in the KA-treated rats and lowered the 5-HT levels both in normal and abnormal conditions. Our findings suggest that the AT1 receptor antagonist exerts disease-modifying effects during KA-induced epileptogenesis and neuronal damage in CA1 hippocampal area, attenuated some of the behavioral changes and restored diurnal variability in locomotor activity.

Effect of chronic treatment with angiotensin receptor ligands on water-salt balance in Wistar and spontaneously hypertensive rats.

UNLABELLED: The renin-angiotensin system plays a crucial role in the regulation of cardiovascular function and maintenance of water-electrolyte balance. The two major receptor types of the system, AT1 and AT2, have different, often opposite effects on these functions. AIM: To elucidate the impact of long-term treatment with selective angiotensin receptor antagonists and an agonist on water-salt balance in normotensive Wistar and spontaneously hypertensive rats (SHRs). MATERIALS AND METHODS: 12-week-old male Wistar rats and SHRs were individually housed in metabolic cages and 24-h food and water intake and urine and electrolyte excretion were measured. Urinary sodium (UNa), potassium (UK) and chlorine (UCl) were determined by a flame photometer. Losartan, a selective AT1 receptor antagonist, was administered in the Wistar rats and SHRs at a dose of 10 mg/kg/day subcutaneously (sc). Wistar rats were also given the AT2 receptor antagonist, PD123319, subcutaneously at a dose of 10 mg/kg/ day. CGP 42112A, an AT2 receptor agonist, was administered intracerebroventricularly in Wistar rats at a dose of 12 microg/rat/day. The drugs were infused continuously for 14 days through osmotic minipumps. RESULTS: Losartan selectively increased sodium excretion in both rat strains and decreased weight gain in SHRs. PD123319 increased potassium excretion and decreased weight gain in Wistar rats. CGP 42112A increased food and water intake, urine output and UNa+ and UK+ excretion and decreased weight gain in normotensive Wistar rats. CONCLUSIONS: Chronic treatment with selective angiotensin receptor ligands modifies water-salt balance in rats through changes both in renal excretory function and ingestive behaviors.

Effect of long-term caffeine administration on depressive-like behavior in rats exposed to chronic unpredictable stress.

Chronic unpredictable stress (CUS) was used to study the effects of a long-term treatment with either caffeine (8 mg/kg, orally) or desipramine (DMI) (10 mg/kg, intraperitoneally) in Wistar rats. The CUS procedure was applied for 6 weeks. Animals underwent a 2-week drug-free CUS procedure. Drugs were administered for 4 weeks alongside the stress and both drug and stress were continued throughout the behavioral testing period. CUS-exposed rats showed depressive-like behavior with reduced weight gain, reduced consumption of sucrose solution, increased immobility in the forced swimming test, and hypolocomotion in an open field. For the open field and elevated plus maze, calculation of an anxiety index confirmed that CUS increased anxiety, which was accompanied by an increase in the core temperature. DMI counteracted these physical and behavioral changes. Caffeine caused similar effects to DMI on weight gain, motor activity, anxiety level, and core temperature. In CUS-exposed rats, caffeine showed antidepressant and anxiolytic activity, accompanied by increased hippocampal dopamine and serotonin levels. However, no significant change in weight gain or core temperature was observed after caffeine treatment in CUS-exposed rats. These results suggest that, similar to the antidepressant DMI, long-term caffeine exposure exerts an antidepressant and anxiolytic effect in the CUS model. The involvement of the dopaminergic and serotonergic systems is discussed.

The effects of chronic losartan pretreatment on restraint stress-induced changes in motor activity, nociception and pentylenetetrazol generalized seizures in rats.

UNLABELLED: Accumulated evidence has shown that renin-angiotensin system has a pivotal role in stress responses. AIM: to assess the participation of AT1 receptor in stress-induced modulation of motor activity, nociception and seizure susceptibility in male Wistar rats. MATERIAL AND METHODS: AT1 receptor antagonist losartan was administered subcutaneously to rats for 10 days at a dose of 10 mg/kg either alone or as a pretreatment before chronic restraint stress applied for 10 days. Locomotor and exploratory activity (open field test), the nociception (paw-pressure test) and the seizure susceptibility (pentylenetetrazol seizure test) were analysed. RESULTS: Chronic restraint stress decreased motor activity and increased anxiety-like behaviour (grooming) while losartan pretreatment alleviated anxiety-like behaviour. Chronic restraint stress had an antinociceptive effect in paw-pressure test and losartan pretreatment abolished stress-induced antinociception. Both chronic restraint stress and losartan showed anticonvulsant activity in pentylenetetrazol seizure test. However, drug pretreatment attenuated this effect in chronically-stressed rats. CONCLUSIONS: Our findings suggest that the AT1 receptor is involved in the mechanism of stress-induced changes in anxiety-like behaviour, nociception and seizure susceptibility in rats.