Effect of Training at Lactate Threshold Intensity on Maximal Time to Exhaustion, Depression and Anxiety Behaviour of Spontaneously Hypertensive Rats after Kainate-Induced Status Epilepticus.

AIM: The objective of the present study was to investigate the effect of treadmill training at lactate threshold intensity on maximum time to exhaustion (MTE) and heart rate (HR) as well as behavioral changes after kainate (KA)-induced status epilepticus (SE) of spontaneously hypertensive rats (SHRs). MATERIALS AND METHODS: Male SHRs were divided in four groups: two sedentary (vehicle- and KA-treated) and two exercised (vehicle- and KA-treated), respectively. The exercised rats were trained on a treadmill at a speed of 20 m.min-1 and 0° elevation for 40 min.d-1, for 4 wk. Maximal time to exhaustion and HR was measured at the beginning and at the end of the training period. Status epilepticus was evoked in half of the sedentary and trained rats by a repetitive intraperitoneal injection of KA in low subconvulsive doses. The other half of the groups received saline. Sucrose preference test (SPT) for depression-like behavior and hole board test (HBT) for impulsivity were performed a month after KA/veh injection. RESULTS: The maximum time of exhaustion was elongated in the SHRs at the end of the training period in comparison with the beginning. However, no effect on HR was detected in trained rats. Kainate treatment after one month of training alleviated the SE-induced anhedonia in SPT and stereotyped behavior in HBT, respectively. CONCLUSIONS: Taken together, these results demonstrate that exercise exerts a beneficial influence on physical working capacity, depression and impulsive behavior in a co-morbid model of essential hypertension and SE.

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.

Early caffeine exposure: transient and long-term consequences on brain excitability.

The influence of pre- and postnatal caffeine treatment on brain excitability during development and adulthood is reviewed. Pre- and postnatal exposure to caffeine induces sex- and age-specific long-term neurochemical alterations in the brain and the behavior of rodents. Because adenosine neuromodulation is closely related to the regulation of brain excitability the increased expression in adenosine receptor system due to neonatal caffeine treatment should cause transient and permanent changes in seizure susceptibility. So far, findings have been focused on primarily developmental changes of the brain adenosine modulatory system and have demonstrated that the alterations are not restricted to a single brain region. Neurobehavioral changes and the anticonvulsant effect of early caffeine exposure are dependent on the caffeine dose, developmental stage of exposure and age of testing. Although outcomes of caffeine treatment are still a matter of debate, our review raise questions concerning the impact of early caffeine treatment on regulation of seizure susceptibility during development and adulthood.

Different effects of postnatal caffeine treatment on two pentylenetetrazole-induced seizure models persist into adulthood.

BACKGROUND: Postnatal treatment with caffeine from P7 to P11 (10 or 20 mg/kg daily) resulted in transient changes in two pentylenetetrazole (PTZ)-induced models of epileptic seizures characterized by spike-and-wave EEG rhythm in immature rats. To know if some changes persist into adulthood we studied these models in young adult Wistar rats. METHODS: Caffeine treatment at a daily dose of 10 and/or 20 mg/kg, sc was executed during postnatal days 7-11. Rhythmic metrazol activity (RMA, model of human absences) was induced in 60-day old rats by two successive doses of PTZ (20 + 20 mg/kg, ip) while for induction of minimal clonic seizures (model of human myoclonic seizures) the second dose of PTZ was 40 mg/kg. RESULTS: RMA episodes elicited by the 20 + 20 mg/kg dose of PTZ in adult rats exposed to caffeine at P7 to P11 were decreased. This effect was more pronounced in group treated with the higher dose of caffeine. In contrast, the lower dose of caffeine exacerbated minimal clonic seizures (both incidence and intensity were increased). In addition, some animals from the 20-mg/kg caffeine group exhibited transition to generalized tonic-clonic seizures. CONCLUSION: Different effects of postnatal caffeine exposure persist into adulthood; the seizure ameliorating effects in a model of absences and seizure exacerbating action in a model of myoclonic seizures are dose-specific.

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.