Epilepsy Seizures in Spontaneously Hypertensive Rats After Acoustic Stimulation: Role of Renin-Angiotensin System.

Hypertension is a common comorbidity observed in individuals with epilepsy. Growing evidence suggests that lower blood pressure is associated with reduced frequency and severity of seizures. In this study, we sought to investigate whether the renin-angiotensin system (RAS), which is a critical regulator of blood pressure, is involved in the pathogenesis of audiogenic epilepsy-related seizures in a hypertensive rat model. Spontaneously hypertensive rats (SHRs) were given RAS inhibitors, angiotensin-converting enzyme (ACE) inhibitor or angiotensin II type I receptor (AT1R) antagonist, for 7 days prior to inducing epileptic seizures by acoustic stimulation. After the pretreatment phase, blood pressure (BP) of SHRs normalized as expected, and there was no difference in systolic and diastolic BP between the pretreated SHRs and normotensive rat group (Wistar). Next, treated and untreated SHRs (a high BP control) were individually subjected to acoustic stimuli twice a day for 2 weeks. The severity of tonic-clonic seizures and the severity of temporal lobe epilepsy seizures (product of forebrain recruitment) were evaluated by the mesencephalic severity index (Rossetti et al. scale) and the limbic index (Racine's scale), respectively. Seizures were observed in both untreated (a high BP control) SHRs and in SHRs treated with AT1R antagonist and ACE inhibitor. There was no statistical difference in the mesencephalic severity and limbic index between these groups. Our results demonstrate that SHRs present seizure susceptibility with acoustic stimulation. Moreover, although RAS inhibitors effectively reduce blood pressure in SHR, they do not prevent developing epileptic seizures upon acoustic stimulation in SHR. In conclusion, our study shows that RAS is an unlikely link between hypertension and susceptibility to epileptic seizures induced by acoustic stimulation in SHRs, which is in contrast with the anticonvulsant effect of losartan in other animal models of epilepsy.

Elucidating the neurotoxicity of the star fruit.

Caramboxin: Patients suffering from chronic kidney disease are frequently intoxicated after ingesting star fruit. The main symptoms of this intoxication are named in the picture. Bioguided chemical procedures resulted in the discovery of caramboxin, which is a phenylalanine-like molecule that is responsible for intoxication. Functional experiments in vivo and in vitro point towards the glutamatergic ionotropic molecular actions of caramboxin, which explains its convulsant and neurodegenerative properties.

Inhibition of the renin-angiotensin system prevents seizures in a rat model of epilepsy.

The RAS (renin-angiotensin system) is classically involved in BP (blood pressure) regulation and water-electrolyte balance, and in the central nervous system it has been mostly associated with homoeostatic processes, such as thirst, hormone secretion and thermoregulation. Epilepsies are chronic neurological disorders characterized by recurrent epileptic seizures that affect 1-3% of the world's population, and the most commonly used anticonvulsants are described to be effective in approx. 70% of the population with this neurological alteration. Using a rat model of epilepsy, we found that components of the RAS, namely ACE (angiotensin-converting enzyme) and the AT1 receptor (angiotensin II type 1 receptor) are up-regulated in the brain (2.6- and 8.2-fold respectively) following repetitive seizures. Subsequently, epileptic animals were treated with clinically used doses of enalapril, an ACE inhibitor, and losartan, an AT1 receptor blocker, leading to a significant decrease in seizure severities. These results suggest that centrally acting drugs that target the RAS deserve further investigation as possible anticonvulsant agents and may represent an additional strategy in the management of epileptic patients.

Neuroethological study of status epilepticus induced by systemic pilocarpine in Wistar audiogenic rats (WAR strain).

The administration of pilocarpine (PILO) is widely recognized as resulting in an experimental model of temporal lobe epilepsy; it is characterized by induction of status epilepticus (SE) and spontaneous recurrent seizures after a latent period. We provide in this work a neuroethological description of the SE induced by PILO. Behavioral evaluations were made in Wistar Audiogenic Rats (WARs) and Wistar resistant (R) animals. The experimental group (R) and WARs were pretreated with methyl scopolamine (1mg/kg ip) and injected with PILO (R animals, 340-380 mg/kg ip; WARs, 240-280 mg/kg ip). Among R animals, 36% developed SE, and among WARs, 53%. The control group (R animals and WARs) was injected only with methyl scopolamine plus saline. The ETHOMATIC method was used for evaluation of seizures. Sequences included in the analysis were chosen using (1) fixed observation windows and (2) behavioral triggers. The R group showed that the threshold for seizure is variable, so seizure onset and behavioral evolution were better described using behavioral triggers than fixed observation windows. The observation windows selected in similar duration intervals do not characterize the seizures. Sequential analysis in the WAR group showed high mortality after SE and greater susceptibility to PILO, compared with R animals. We conclude that with neuroethological tools it is possible to better map the sequence and evolution of SE induced by PILO compared to only using behavioral and arbitrary seizure severity scales. This sequence is faster and stronger in severity when WARs are compared with R animals. Although the WARs underwent an evolution of SE in some way equivalent to that of R animals, some rats presented tonic-clonic convulsions after PILO injection, very similar to acute audiogenic seizures, a brainstem-dependent model. The current data also point to the PILO-plus-WAR combination as a suitable protocol to study the genetic-epilepsy connection in experimental temporal lobe epilepsy.

Behavioral, morphologic, and electroencephalographic evaluation of seizures induced by intrahippocampal microinjection of pilocarpine.

PURPOSE: We studied, by means of video-EEG and neo-Timm histochemistry, the behavioral, electrophysiologic, and structural characteristics of seizures induced by intrahippocampal microinjection of pilocarpine (HIP-PILO), a selective model of temporal lobe epilepsy (TLE). METHODS: We investigated the behavioral and electrophysiologic (hippocampus and amygdala EEG) evaluation of status epilepticus (SE) induced by HIP-PILO and the consequent spontaneous recurrent seizures (SRSs). We evaluated hippocampal structural rearrangements after SE by means of neo-Timm staining. RESULTS: HIP-PILO induced SE in 17 (71%) of 24 animals. Although three animals displayed spontaneous remission of SE (not used in analysis) before the established SE duration (90 min), none of those undergoing SE died. Of SE animals, 10 (71%) of 14 had SRSs. All animals with SE had clear-cut mossy fiber sprouting (MFS) in the inner molecular layer of the dentate gyrus and epileptiform activity in hippocampus and amygdala. CONCLUSIONS: HIP-PILO rats displayed SE, SRS, MFS, and limbic epileptiform activity, without animal loss after SE. Thus, our data support this as a selective and efficient model of TLE.

Análise neuroetológica do desenvolvimento de kindling audiogênico em ratos wistar / Neuroethological analisis of the development of audiogenic kindling in wistar rats

A estimulaçäo repetida sublimiar experimental de áreas límbicas leva ao desenvolvimento de convulsöes generalizadas, inclusive motoras e permanentes, fenômeno conhecido como kindling. De outro lado a estimulaçäo acústica de animais sensíveis pode induzir convulsöes tônico-clônicas generalizadas, conhecidas como convulsöes audiogênicas (CA). A repetiçäo de CA pode recrutar áreas prosencefálicas, modelo conhecido como kindling audiogênico. Nas CA agudas, o colículo inferior é a área inferior mais crítica envolvida na origem de atividade epileptiforme, enquanto que no kindling audiogênico, a amígdala e o córtex cerebral podem ser recrutados. A evoluçäo comportamental indicativa desse recrutamento foi avaliada mediante o uso de técnicas neuroetológicas