Proconvulsant effects of sildenafil citrate on pilocarpine-induced seizures: Involvement of cholinergic, nitrergic and pro-oxidant mechanisms

Carvalho, Michelle Garcêz de; Chaves-Filho, Adriano José Maia; Souza, Alana Gomes de; Lima, Camila Nayane de Carvalho; Lima, Klistenes Alves de; Vasconcelos, Emiliano Ricardo Rios; Feitosa, Mariana Lima; Oliveira, João Almir; Souza, Denia Alves Albuquerque de; Macedo, Danielle; Fonteles, Marta Maria de França

doi:10.1016/j.brainresbull.2019.04.008

Cited by 10 publications

(7 citation statements)

References 86 publications

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“…Each nude mouse was inoculated subcutaneously with 0.2 ml of the cell suspension. As described by de Carvalho et al [ 25 ], the mice were repeatedly administered sildenafil (2. 5, 5, 10 and 20 mg/kg) by oral gavage for 7 days.…”

Section: Methodsmentioning

confidence: 99%

Sildenafil Inhibits the Growth and Epithelial-to-mesenchymal Transition of Cervical Cancer via the TGF-β1/Smad2/3 Pathway

Liu

Pei

et al. 2023

CCDT

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Aims: To explore new potential treatment for cervical cancer. Background: Cervical cancer is the second most common cancer in women, causing >250,000 deaths worldwide. Patients with cervical cancer are mainly treated with platinum compounds, which often cause severe toxic reactions. Furthermore, the long-term use of platinum compounds can reduce the sensitivity of cancer cells to chemotherapy and increase the drug resistance of cervical cancer. Therefore, exploring new treatment options is meaningful for cervical cancer. Objective: The present study was to investigate the effect of sildenafil on the growth and epithelial-to-mesenchymal transition (EMT) of cervical cancer. Objective: Objective: The present study was to investigate the effect of sildenafil on the growth and epithelial-to-mesenchymal transition (EMT) of cervical cancer. Methods: HeLa and SiHa cells were treated with sildenafil for different durations. Cell viability, clonogenicity, wound healing and Transwell assays were performed. The levels of transforming growth factor-β1 (TGF-β1), transforming growth factor-β type I receptor (TβRI), phosphorylated (p-)Smad2 and p-Smad3 in cervical cancer samples were measured. TGF-β1, Smad2 or Smad3 were overexpressed in HeLa cells, and we measured the expression of EMT marker proteins and the changes in cell viability, colony formation, etc. Finally, HeLa cells were used to establish a nude mouse xenograft model with sildenafil treatment. The survival rate of mice and the tumor size were recorded. Results: Results: High concentrations of sildenafil (1.0-2.0 μM) reduced cell viability and the number of HeLa and SiHa colonies and the invasion/migration ability of HeLa and SiHa cells in a dose- and time-dependent manner. The expression of TGF-β1, TβRI, p-Smad2 and p-Smad3 was significantly enhanced in cervical cancer samples and cervical cancer cell lines. Sildenafil inhibited the expression of TGF-β1-induced EMT marker proteins (Snail, vimentin, Twist, E-cadherin and N-cadherin) and p-Smad2/3 in HeLa cells. Overexpression of TGF-β1, Smad2 and Smad3 reversed the effect of sildenafil on EMT, viability, colony formation, migration and invasion ability of HeLa cells. In the in vivo study, sildenafil significantly increased mouse survival rates and suppressed xenograft growth. Conclusion: Sildenafil inhibits the proliferation, invasion ability and EMT of human cervical cancer cells by regulating the TGF-β1/Smad2/3 pathway.

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Section: Methodsmentioning

confidence: 99%

Sildenafil Inhibits the Growth and Epithelial-to-mesenchymal Transition of Cervical Cancer via the TGF-β1/Smad2/3 Pathway

Liu

Pei

et al. 2023

CCDT

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“…Pilocarpine is a potent muscarinic receptor agonist [48] used to induce chronic seizure-like conditions [49,50], where the underlying mechanism depends on activation of the muscarinic receptor (M1) and seizures are further maintained by N-methyl-d-aspartate (NMDA) receptors' activation [51]. Status epilepticus (SE) is defined as a constant or sporadic seizure that lasts for more than 5 min, without a complete recovery of consciousness between seizures [52].…”

Section: Alpha-synuclein-mediated Neurodegeneration: Implication In Epileptogenesismentioning

confidence: 99%

Revisiting the Impact of Neurodegenerative Proteins in Epilepsy: Focus on Alpha-Synuclein, Beta-Amyloid, and Tau

Paudel

Angelopoulou

Piperi

et al. 2020

Biology

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Lack of disease-modifying therapy against epileptogenesis reflects the complexity of the disease pathogenesis as well as the high demand to explore novel treatment strategies. In the pursuit of developing new therapeutic strategies against epileptogenesis, neurodegenerative proteins have recently gained increased attention. Owing to the fact that neurodegenerative disease and epileptogenesis possibly share a common underlying mechanism, targeting neurodegenerative proteins against epileptogenesis might represent a promising therapeutic approach. Herein, we review the association of neurodegenerative proteins, such as α-synuclein, amyloid-beta (Aβ), and tau protein, with epilepsy. Providing insight into the α-synuclein, Aβ and tau protein-mediated neurodegeneration mechanisms, and their implication in epileptogenesis will pave the way towards the development of new agents and treatment strategies.

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“…This potentiates the endogenous effects of NO, synthesized by nitric oxide synthetase (NOS), which activates guanylate cyclase (GC) and induces cyclic guanosine monophosphate (cGMP) production. This mechanism causes relaxation of the smooth muscles of the penis and arterial dilation, promoting erection by distending the corpora cavernosa [ 20 , 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…According to de Carvalho et al [ 20 ], Sildenafil lowers the epileptic threshold which could be related to increased cholinergic and nitrergic activity in the brain. Nieoczym et al [ 15 ] noted that Sildenafil did not significantly influence the focal seizure threshold in the rat model with amygdala epilepsy, nor did it influence seizure severity and had weak anticonvulsant action.…”

Section: Discussionmentioning

confidence: 99%

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Unmasking hidden risks: The surprising link between PDE5 inhibitors and seizure susceptibility

Silva,

Nascimento,

Azevedo

et al. 2023

PLoS ONE

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Background Phosphodiesterase 5 inhibitors (PDE5i) are the first line treatment for erectile dysfunction; however, several articles and case reports have shown central nervous system effects, that can cause seizures in susceptible patients. This study aims to describe the changes caused by the use of Sildenafil and Tadalafil through the analysis of abnormalities expressed in the electrocorticogram (ECoG) of rats and evaluate the seizure threshold response and treatment of seizures with anticonvulsants. Materials and methods The study used 108 rats (Wistar). Before surgery for electrode placement in dura mater, the animals were randomly separated into 3 experiments for electrocorticogram analysis. Experiment 1: ECoG response to using PD5i (Sildenafil 20mg/kg and Tadalafil 2.6mg/kg p.o.). Experiment 2: ECoG response to the use of PD5i in association with Pentylenetetrazole (PTZ—30 mg/kg i.p.), a convulsive model. Experiment 3: ECoG response to anticonvulsant treatment (Phenytoin, Phenobarbital and Diazepam) of seizures induced by association IPDE5 + PTZ. All recordings were made thirty minutes after administration of the medication and analyzed for ten minutes, only once. We considered statistical significance level of *p<0.05, **p<0.01 and ***p < 0.001. Results After administration of Sildenafil and Tadalafil, there were increases in the power of recordings in the frequency bands in oscillations in alpha (p = 0.0920) and beta (p = 0.602) when compared to the control group (p<0.001). After the use of Sildenafil and Tadalafil associated with PTZ, greater potency was observed in the recordings during seizures (p<0.001), however, the Sildenafil group showed greater potency when compared to Tadalafil (p<0.05). Phenobarbital and Diazepam showed a better response in controlling discharges triggered by the association between proconvulsant drugs. Conclusions PDE5i altered the ECoG recordings in the rats’ motor cortexes, demonstrating cerebral asynchrony and potentiating the action of PTZ. These findings demonstrate that PDE5i can lower the seizure threshold.

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Proconvulsant effects of sildenafil citrate on pilocarpine-induced seizures: Involvement of cholinergic, nitrergic and pro-oxidant mechanisms

Cited by 10 publications

References 86 publications

Sildenafil Inhibits the Growth and Epithelial-to-mesenchymal Transition of Cervical Cancer via the TGF-β1/Smad2/3 Pathway

Sildenafil Inhibits the Growth and Epithelial-to-mesenchymal Transition of Cervical Cancer via the TGF-β1/Smad2/3 Pathway

Revisiting the Impact of Neurodegenerative Proteins in Epilepsy: Focus on Alpha-Synuclein, Beta-Amyloid, and Tau

Unmasking hidden risks: The surprising link between PDE5 inhibitors and seizure susceptibility

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