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

Abstract

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.

Anti-Epileptogenic Effects of Antiepileptic Drugs

“…Its beneficial effects upon spontaneous seizure activity was associated with a clear cut neuroprotective activity found in the CA3 hippocampal area and the septo-temporal hilus of the dentate gyrus. Unlike the former study [35] losartan-treated animals still displayed behavioral disturbances evaluated in the four mentioned above behavioral tests [36]. Amygdala-kindled seizures in rats may be regarded as a model of epileptogenesis as a number of subconvulsive electrical stimulations eventually results in progressive seizure activity [37].…”

“…Basically, the experimental approach was comparable to that of the previous study [35]. The only difference concerned spontaneously hypertensive rats because the authors intended to study the influence of losartan in a model of co-existing hypertension and epilepsy, following kainate-induced SE [36]. The AT1 receptor antagonist extended the latency to the onset of spontaneous seizures, also reducing their frequency and duration.…”

Pharmacological targeting of brain inflammation in epilepsy: Therapeutic perspectives from experimental and clinical studies

“…86,91 Accordingly, a transient post-injury treatment with losartan, an angiotensin II type 1 receptor antagonist that blocks TGF-b signaling, reduces incidence and severity of epilepsy as well as cell loss, BBB dysfunction, and neuroinflammation in rodent models of acquired vascular injury and SE. [92][93][94] Moreover, losartan attenuates spontaneous seizure frequency and neuronal cell loss in spontaneously hypertensive rats exposed to SE 95 and improved cognitive functions and neural damage after traumatic brain injury (TBI). 96…”

The Role of Sartans in the Treatment of Stroke and Subarachnoid Hemorrhage: A Narrative Review of Preclinical and Clinical Studies

“…Here, an additive direct antagonism on these receptors could reduce the sensitivity to an AT 2 -1-R-mediated vasocontraction to angiotensin II, too [125,134]. LS possesses beneficial aspects on cerebral epileptogenicity, which could be applied to the issue of reducing cortical spreading depression post aSAH [135][136][137][138]. Also, it is able to restore post-ischemic cerebral autoregulation after hemorrhagic stroke [134].…”