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

Pereira, Marilia G.A.G.; Becari, Christiane; Oliveira, José Antônio Cortes de; Salgado, Maria Cristina O.; García-Cairasco, Norberto; Costa-Neto, Cláudio M.

doi:10.1042/cs20100053

Cited by 72 publications

(68 citation statements)

References 30 publications

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“…However, results using inhibition of ACE and antagonists of AngII receptors suggest a pro-convulsant action of AngII in the brain. AngII receptor antagonists showed anti-convulsant affects in pentylenetetrazol treated rats [248] and both AngII receptor antagonists and ACE antagonists attenuated audiogenic seizures [242]. Moreover, the effects of known antiepileptics were potentiated by AngII receptor antagonists in electroshock seizures [249,250] and by ACE inhibitors in audiogenic seizures [251].…”

Section: Angiotensinsmentioning

confidence: 89%

“…Originally described in the hypothalamus related to the control of fluid intake [237], the RAS has also been identified in other brain regions, too, including the cortex and the hippocampus [238][239][240]. Furthermore, the levels of components of the RAS were changed in the hippocampus following pilocarpine treatment of rats [241] and audiogenic seizures [242] as well as in human temporal lobe epilepsy [243]. Initial studies of a research group suggested anti-convulsant actions of Ang peptides against pentylenetetrazol-induced seizures [244] reviewed recently [245].…”

Section: Angiotensinsmentioning

confidence: 99%

“…AT4 is the most abundant in the cortex and the hippocampus [236]. Elevated mRNA expression was shown for AT1 but not for AT2 following audiogenic seizures [242] and in temporal lobe epilepsy [243], while no data are available for AT4. Furthermore, specific AT1 antagonists had anti-convulsant properties in animal models of epilepsy [242,[248][249][250].…”

Section: Angiotensinsmentioning

confidence: 99%

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Receptors of Peptides as Therapeutic Targets in Epilepsy Research

Dobolyi¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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Neuropeptides are signaling molecules participating in the modulation of synaptic transmission. Neuropeptides are stored in dense core synaptic vesicles, the release of which requires profound excitation. Only in the extracellular space, neuropeptides act on G-protein coupled receptors to exert a relatively slow action both pre-and postsynaptically. Consequently, neuropeptide modulators are ideal candidates to influence epileptic tissue overexcited during seizures. Indeed, a number of neuropeptides have been implicated in epilepsy and many of them are considered to have endogenous neuroprotective actions. Neuropeptides, present in the hippocampus, the most frequent focus of seizures in temporal lobe epilepsy, received the largest attention as potential anti-epileptic substances. Hippocampal neuropeptides, somatostatin, neuropeptide Y, galanin, dynorphin, enkephalin, substance P, cholecystokinin, vasoactive intestinal polypeptide, and some neuropeptides, which are also hormones such as ghrelin, angiotensins, corticotropin-releasing hormone, adrenocorticotropin, thyrotropin-releasing hormone, oxytocin and vasopressin involved in epilepsy are discussed in the review article. Oral application of neuropeptides as drugs is typically not efficient because of low bioavailability: rapid degradation and insufficient penetration through the blood-brain barrier. Recent progress in the development of non-peptide agonists and antagonists of neuropeptide receptors as well as gene therapeutic approaches leading to the local production of neuropeptides within the central nervous system will also be discussed.

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Section: Angiotensinsmentioning

confidence: 89%

Section: Angiotensinsmentioning

confidence: 99%

Section: Angiotensinsmentioning

confidence: 99%

See 1 more Smart Citation

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

Dobolyi¹,

Kékesi²,

Juhász³

et al. 2014

CMC

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“…Moreover, treatment with losartan (AT 1 receptor antagonist) was capable of decreasing the severity of seizures of WARs with TLE. 28 On the basis of those studies, we aimed to investigate the metabolism of AngI in the hippocampus and related enzymatic pathways. We first show that Ang-(1-7) is the AngI metabolite that is preferentially generated by hippocampal enzymes; second, we show that TOP is one of the major enzymes involved in the AngI metabolism, and it is responsible for ≈50% of the Ang-(1-7) formation in the hippocampus.…”

Section: Hypertensionmentioning

confidence: 99%

Angiotensin II–Independent Angiotensin-(1–7) Formation in Rat Hippocampus

et al. 2013

Self Cite

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The involvement and relevance of the renin–angiotensin system have been established clearly in cardiovascular diseases, and renin–angiotensin system involvement has also been investigated extensively in the central nervous system. Angiotensin II acts classically by binding to the AT 1 and AT 2 receptors. However, other pathways within the renin–angiotensin system have been described more recently, such as one in which angiotensin-(1–7) (Ang-(1–7)) binds to the receptor Mas. In the central nervous system specifically, it has been reported that this heptapeptide is involved in learning and memory processes that occur in central limbic regions, such as the hippocampus. Therefore, this prompted us to investigate the possible role of the Ang-(1–7)–receptor Mas pathway in epileptic seizures, which are also known to recruit limbic areas. In the present study, we show that Ang-(1–7) is the main metabolite of angiotensin I in rat hippocampi, and, strikingly, that thimet oligopeptidase is the main enzyme involved in the generation of Ang-(1–7). Furthermore, elevations in the levels of thimet oligopeptidase, Ang-(1–7), and of receptor Mas transcripts are observed in chronically stimulated epileptic rats, which suggest that the thimet oligopeptidase–Ang-(1–7)–receptor Mas axis may have a functional relevance in the pathophysiology of these animals. In summary, our data, which describe a new preferential biochemical pathway for the generation of Ang-(1–7) in the central nervous system and an increase in the levels of various elements of the related thimet oligopeptidase–Ang-(1–7)–receptor Mas pathway, unveil potential new roles of the renin–angiotensin system in central nervous system pathophysiology.

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“…8 In a rat model of epilepsy, it was found that components of the RAS, namely ACE and the AT1 receptors are up-regulated in the brain following repetitive seizures. 9 Angiotensin has also been shown to modulate the voltage dependent delayed rectifier potassium current (IK) and IA. 10 Reports suggest higher incidence of seizures in presence of pre-existing chronic inflammatory disorders.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of anticonvulsant activity of ACE inhibitors (imidapril and quinapril) in experimentally induced animal models of epilepsy

Poornima

et al. 2016

Int J Basic Clin Pharmacol

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INTRODUCTIONEpilepsy is a chronic neurological disorder characterized by an enduring predisposition to generate seizures, may be associated with emotional and cognitive dysfunction. This disorder affects 50 million people worldwide and hence, is one of the most common neurological disorder. Despite the availability of a wide range of antiepileptic drugs (AEDs), about one-third of individuals with epilepsy still experience seizures that do not respond to medication.2 Thus, an urgent need exist for effective therapies to be developed. In spite of the vast number of drugs introduced for the treatment of epilepsy, there is still a need for an ideal antiepileptic agent with broad spectrum of activity, rapid onset of action, more economical and least side effects.Epilepsy may be associated with other comorbid conditions like hypertension, diabetes, renal disorders etc. Many researches are in progress, to prove if the drugs used for these disorders like ACE inhibitors, calcium channel blockers, AT II receptor antagonist etc. have any effect on seizure prevention. ABSTRACTBackground: Epilepsy is a chronic neurological disorder characterized by an enduring predisposition to generate seizures, may be associated with emotional and cognitive dysfunction. Objective of this study was to evaluate and compare the anticonvulsant activity of different doses of imidapril and quinapril in animal models of epilepsy. Methods: Swiss albino mice weighing around 25-30g of either sex were divided into 6 groups: control (R.O-10 ml/kg), standard-sodium valproate (40 mg/kg), Q1-quinapril (1.5 mg/kg), Q2-quinapril (10.4 mg/kg), I1-imidapril (0.65mg/kg) and I2-imidapril (2.6 mg/kg). 1 hour after administration of control, test and standard drugs (orally) test was conducted. Convulsions were induced by administering PTZ (70 mg/kg-i.p.) in PTZ model. Seizure latency was the parameter recorded. In MES model, maximal seizures were evoked by supra maximal electroshock stimulation of 50 mA, 50 HZ for 0.2 seconds by using conventional electro convulsion meter. Suppression of tonic hind limb extension was taken as measure of efficacy. Results: The results were analysed by one-way-ANOVA followed by Bonferroni's multiple comparison test. In MES test, dose dependently quinapril and imidapril significantly reduced the duration of tonic hind limb extension in comparison to control (p<0.05) percentage inhibition of seizures by I2 is 58.1%, I1-38.6%, Q2-19.7% and Q1-12.2% with maximum inhibition of seizure produced by I2 in comparison to control in MES test. In PTZ test, dose dependently quinapril and imidapril produced significant increase in seizure latency (p<0.05). Percentage inhibition of seizures by I2-65.8%, I1-59.3%, Q2-50.9% and Q1-33.5% in comparison to control. Conclusions: Quinapril and imidapril in a dose dependent manner showed increase in antiepileptic activity, imidapril has better antiepileptic activity when compared to quinapril.

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

Cited by 72 publications

References 30 publications

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

Angiotensin II–Independent Angiotensin-(1–7) Formation in Rat Hippocampus

Evaluation of anticonvulsant activity of ACE inhibitors (imidapril and quinapril) in experimentally induced animal models of epilepsy

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