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

Ivanova, Natasha; Atanasova, Dimitrinka; Pechlivanova, Daniela; Mitreva, Rumyana; Lazarov, Nikolai; Stoynev, Alexander; Tchekalarova, Jana

doi:10.1016/j.yebeh.2015.06.036

Cited by 11 publications

(8 citation statements)

References 43 publications

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“…Accordingly, different experimental models of TLE present behavioral changes, such as learning disabilities, increased locomotor/exploratory activity, impulsive behavior, and greater aggressiveness. Together, both EPM and OF results showed low anxiety behavior and increased locomotion and exploration of rats with TLE, corroborating several experimental studies [23,[48][49][50].…”

Section: Discussionsupporting

confidence: 87%

“…However, further studies are necessary to better clarify the mechanism involved in these behavioral changes of TLE. The behavioral changes in experimental TLE models are modulated by RAS, since long-term icv Ang II infusion increased the impulsivity and hyperactivity behaviors in rats with TLE induced by the kainic acid model [48]. Additionally, treatment with losartan (selective AT 1 R antagonist) positively affected behavioral disorders caused by this TLE model [28].…”

Section: Discussionmentioning

confidence: 99%

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Antiepileptic effects of long-term intracerebroventricular infusion of angiotensin-(1-7) in an animal model of temporal lobe epilepsy

et al. 2020

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Temporal lobe epilepsy (TLE) is the most frequent type of epilepsy and is often refractory to pharmacological treatment. In this scenario, extensive research has identified components of the renin–angiotensin system as potential therapeutic targets. Therefore, the aim of this study was to evaluate the effects of long-term treatment with Ang-(1-7) in male Wistar rats with TLE induced by pilocarpine. Rats with TLE were submitted to intracerebroventricular infusion of Ang-(1-7) (200 ng/kg/h) for 28 days, starting at the first spontaneous motor seizure (SMS). Body weight, food intake, and SMS were evaluated daily. Behavioral tests and hippocampal protein levels were also evaluated at the end of the treatment. Ang-(1-7) treatment reduced the frequency of SMS and attenuated low anxiety levels, increased locomotion/exploration, and reduced body weight gain that was induced by TLE. Moreover, Ang-(1-7) positively regulated the hippocampal levels of antioxidant protein catalase and antiapoptotic protein Bcl-2, as well as mTOR phosphorylation, which were reduced by TLE. The hippocampal upregulation of angiotensin type 1 receptor induced by TLE was also attenuated by Ang-(1-7), while the Mas receptor was downregulated compared to epilepsy. These data show that Ang-(1-7) presents an antiepileptic effect, increasing neuroprotection markers and reducing SMS frequency, body weight, and behavior impairments found in TLE. Therefore, Ang-(1-7) is a promising coadjutant therapeutic option for the treatment of TLE.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Antiepileptic effects of long-term intracerebroventricular infusion of angiotensin-(1-7) in an animal model of temporal lobe epilepsy

et al. 2020

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“…The beneficial effects of Ang II and IV in neuroplasticity, cognitive function and epilepsy, through the activation of ATR2 and ATR4 with appropriate ligands in animal models, have been acknowledged, creating space for the development of novel therapeutic targets for the treatment of epilepsy and memory impairment [86]. Furthermore, a long-term intracerebroventricular (ICV) infusion with Ang II in kainate-induced status epilepticus results in decreased latency in the onset of first spontaneous motor seizures (SMS) and increased SMS frequency, although it has also shown a neuroprotective role in neural damage in the hippocampus and this infusion exacerbated epileptogenesis through kainate-induced hyperactivity, and induced depressive behavior [87]. There have been some positive findings for other neuropeptides, including apelin, as an endogenous ligand of angiotensin receptor-like 1 (APJ) in the PTZ-induced epilepsy model, and the reduction of APJ with apelin-13 in the PTZ group has indicated anticonvulsive (seizure-inhibition threshold, tonic–clonic latency) and neuroprotective properties that further enhance the role of angiotensinogen pathway targeting in epileptogenesis [88].…”

Section: Impact Of Ras In Epilepsymentioning

confidence: 99%

Role of the Angiotensin Pathway and its Target Therapy in Epilepsy Management

Krasniqi

Daci

2019

IJMS

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Despite extensive research on epileptogenesis, there is still a need to investigate new pathways and targeted therapeutic approaches in this complex process. Inflammation, oxidative stress, neurotoxicity, neural cell death, gliosis, and blood–brain barrier (BBB) dysfunction are the most common causes of epileptogenesis. Moreover, the renin–angiotensin system (RAS) affects the brain’s physiological and pathological conditions, including epilepsy and its consequences. While there are a variety of available pharmacotherapeutic approaches, information on new pathways is in high demand and the achievement of treatment goals is greatly desired. Therefore, targeting the RAS presents an interesting opportunity to better understand this process. This has been supported by preclinical studies, primarily based on RAS enzyme, receptor-inhibition, and selective agonists, which are characterized by pleiotropic properties. Although there are some antiepileptic drugs (AEDs) that interfere with RAS, the main targeted therapy of this pathway contributes in synergy with AEDs. However, the RAS-targeted treatment alone, or in combination with AEDs, requires clinical studies to contribute to, and clarify, the evidence on epilepsy management. There is also a genetic association between RAS and epilepsy, and an involvement of pharmacogenetics in RAS, so there are possibilities for the development of new diagnostic and personalized treatments for epilepsy.

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“…Although WARs have been genetically developed initially for the epilepsy phenotype, they display, in addition to neuropsychiatric comorbidities (Garcia-Cairasco et al, 2017), systemic cardiovascular alterations (Fazan et al, 2015) and impaired central respiratory chemoreflex (Totola et al, 2017). Other groups have shown RAS contribution to epilepsy using animal models such as the kainate (KA) model of temporal lobe epilepsy (TLE) and the pilocarpine in Wistar and SHR (Mello et al, 1993;Scorza et al, 2005;Ivanova et al, 2015;Tchekalarova et al, 2016;Atanasova et al, 2018;Grosser et al, 2020). Interestingly, the long-term treatment with losartan after kainate (KA)-induced status epilepticus (SE) exerted a diseasemodifying effect on spontaneous seizure activity and neuronal damage in a SHR (Tchekalarova et al, 2014(Tchekalarova et al, , 2015(Tchekalarova et al, , 2016.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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

Cited by 11 publications

References 43 publications

Antiepileptic effects of long-term intracerebroventricular infusion of angiotensin-(1-7) in an animal model of temporal lobe epilepsy

Antiepileptic effects of long-term intracerebroventricular infusion of angiotensin-(1-7) in an animal model of temporal lobe epilepsy

Role of the Angiotensin Pathway and its Target Therapy in Epilepsy Management

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

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