Activation of M1 muscarinic acetylcholine receptors by proline-rich oligopeptide 7a (<EDGPIPP) from Bothrops jararaca snake venom rescues oxidative stress-induced neurotoxicity in PC12 cells
Abstract Background: The bioactive peptides derived from snake venoms of the Viperidae family species have been promising as therapeutic candidates for neuroprotection due to their ability to prevent neuronal cell loss, injury, and death. Therefore, this study aimed to evaluate the cytoprotective...
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| Format: | Article |
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SciELO
2024-02-01
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| Series: | Journal of Venomous Animals and Toxins including Tropical Diseases |
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| Online Access: | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1678-91992024000100302&tlng=en |
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| author | Carlos Alberto-Silva Halyne Queiroz Pantaleão Brenda Rufino da Silva Julio Cezar Araujo da Silva Marcela Bermudez Echeverry |
| author_facet | Carlos Alberto-Silva Halyne Queiroz Pantaleão Brenda Rufino da Silva Julio Cezar Araujo da Silva Marcela Bermudez Echeverry |
| author_sort | Carlos Alberto-Silva |
| collection | DOAJ |
| description | Abstract Background: The bioactive peptides derived from snake venoms of the Viperidae family species have been promising as therapeutic candidates for neuroprotection due to their ability to prevent neuronal cell loss, injury, and death. Therefore, this study aimed to evaluate the cytoprotective effects of a synthetic proline-rich oligopeptide 7a (PRO-7a; <EDGPIPP) from Bothrops jararaca snake, on oxidative stress-induced toxicity in neuronal PC12 cells and astrocyte-like C6 cells. Methods: Both cells were pre-treated for four hours with different concentrations of PRO-7a, submitted to H2O2-induced damage for 20 h, and then the oxidative stress markers were analyzed. Also, two independent neuroprotective mechanisms were investigated: a) L-arginine metabolite generation via argininosuccinate synthetase (AsS) activity regulation to produce agmatine or polyamines with neuroprotective properties; b) M1 mAChR receptor subtype activation pathway to reduce oxidative stress and neuron injury. Results: PRO-7a was not cytoprotective in C6 cells, but potentiated the H2O2-induced damage to cell integrity at a concentration lower than 0.38 μM. However, PRO-7a at 1.56 µM, on the other hand, modified H2O2-induced toxicity in PC12 cells by restoring cell integrity, mitochondrial metabolism, ROS generation, and arginase indirect activity. The α-Methyl-DL-aspartic acid (MDLA) and L-NΩ-Nitroarginine methyl ester (L-Name), specific inhibitors of AsS and nitric oxide synthase (NOS), which catalyzes the synthesis of polyamines and NO from L-arginine, did not suppress PRO-7a-mediated cytoprotection against oxidative stress. It suggested that its mechanism is independent of the production of L-arginine metabolites with neuroprotective properties by increased AsS activity. On the other hand, the neuroprotective effect of PRO-7a was blocked in the presence of dicyclomine hydrochloride (DCH), an M1 mAChR antagonist. Conclusions: For the first time, this work provides evidence that PRO-7a-induced neuroprotection seems to be mediated through M1 mAChR activation in PC12 cells, which reduces oxidative stress independently of AsS activity and L-arginine bioavailability. |
| first_indexed | 2024-03-07T23:35:31Z |
| format | Article |
| id | doaj.art-794c5a6d9f244d2487c5e53839abe6c1 |
| institution | Directory Open Access Journal |
| issn | 1678-9199 |
| language | English |
| last_indexed | 2024-03-07T23:35:31Z |
| publishDate | 2024-02-01 |
| publisher | SciELO |
| record_format | Article |
| series | Journal of Venomous Animals and Toxins including Tropical Diseases |
| spelling | doaj.art-794c5a6d9f244d2487c5e53839abe6c12024-02-20T07:38:23ZengSciELOJournal of Venomous Animals and Toxins including Tropical Diseases1678-91992024-02-013010.1590/1678-9199-jvatitd-2023-0043Activation of M1 muscarinic acetylcholine receptors by proline-rich oligopeptide 7a (<EDGPIPP) from Bothrops jararaca snake venom rescues oxidative stress-induced neurotoxicity in PC12 cellsCarlos Alberto-Silvahttps://orcid.org/0000-0003-4519-8930Halyne Queiroz PantaleãoBrenda Rufino da SilvaJulio Cezar Araujo da SilvaMarcela Bermudez EcheverryAbstract Background: The bioactive peptides derived from snake venoms of the Viperidae family species have been promising as therapeutic candidates for neuroprotection due to their ability to prevent neuronal cell loss, injury, and death. Therefore, this study aimed to evaluate the cytoprotective effects of a synthetic proline-rich oligopeptide 7a (PRO-7a; <EDGPIPP) from Bothrops jararaca snake, on oxidative stress-induced toxicity in neuronal PC12 cells and astrocyte-like C6 cells. Methods: Both cells were pre-treated for four hours with different concentrations of PRO-7a, submitted to H2O2-induced damage for 20 h, and then the oxidative stress markers were analyzed. Also, two independent neuroprotective mechanisms were investigated: a) L-arginine metabolite generation via argininosuccinate synthetase (AsS) activity regulation to produce agmatine or polyamines with neuroprotective properties; b) M1 mAChR receptor subtype activation pathway to reduce oxidative stress and neuron injury. Results: PRO-7a was not cytoprotective in C6 cells, but potentiated the H2O2-induced damage to cell integrity at a concentration lower than 0.38 μM. However, PRO-7a at 1.56 µM, on the other hand, modified H2O2-induced toxicity in PC12 cells by restoring cell integrity, mitochondrial metabolism, ROS generation, and arginase indirect activity. The α-Methyl-DL-aspartic acid (MDLA) and L-NΩ-Nitroarginine methyl ester (L-Name), specific inhibitors of AsS and nitric oxide synthase (NOS), which catalyzes the synthesis of polyamines and NO from L-arginine, did not suppress PRO-7a-mediated cytoprotection against oxidative stress. It suggested that its mechanism is independent of the production of L-arginine metabolites with neuroprotective properties by increased AsS activity. On the other hand, the neuroprotective effect of PRO-7a was blocked in the presence of dicyclomine hydrochloride (DCH), an M1 mAChR antagonist. Conclusions: For the first time, this work provides evidence that PRO-7a-induced neuroprotection seems to be mediated through M1 mAChR activation in PC12 cells, which reduces oxidative stress independently of AsS activity and L-arginine bioavailability.http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1678-91992024000100302&tlng=enBothrops jararacaNeuroprotectionBioactive peptideProline-rich oligopeptide |
| spellingShingle | Carlos Alberto-Silva Halyne Queiroz Pantaleão Brenda Rufino da Silva Julio Cezar Araujo da Silva Marcela Bermudez Echeverry Activation of M1 muscarinic acetylcholine receptors by proline-rich oligopeptide 7a (<EDGPIPP) from Bothrops jararaca snake venom rescues oxidative stress-induced neurotoxicity in PC12 cells Journal of Venomous Animals and Toxins including Tropical Diseases Bothrops jararaca Neuroprotection Bioactive peptide Proline-rich oligopeptide |
| title | Activation of M1 muscarinic acetylcholine receptors by proline-rich oligopeptide 7a (<EDGPIPP) from Bothrops jararaca snake venom rescues oxidative stress-induced neurotoxicity in PC12 cells |
| title_full | Activation of M1 muscarinic acetylcholine receptors by proline-rich oligopeptide 7a (<EDGPIPP) from Bothrops jararaca snake venom rescues oxidative stress-induced neurotoxicity in PC12 cells |
| title_fullStr | Activation of M1 muscarinic acetylcholine receptors by proline-rich oligopeptide 7a (<EDGPIPP) from Bothrops jararaca snake venom rescues oxidative stress-induced neurotoxicity in PC12 cells |
| title_full_unstemmed | Activation of M1 muscarinic acetylcholine receptors by proline-rich oligopeptide 7a (<EDGPIPP) from Bothrops jararaca snake venom rescues oxidative stress-induced neurotoxicity in PC12 cells |
| title_short | Activation of M1 muscarinic acetylcholine receptors by proline-rich oligopeptide 7a (<EDGPIPP) from Bothrops jararaca snake venom rescues oxidative stress-induced neurotoxicity in PC12 cells |
| title_sort | activation of m1 muscarinic acetylcholine receptors by proline rich oligopeptide 7a edgpipp from bothrops jararaca snake venom rescues oxidative stress induced neurotoxicity in pc12 cells |
| topic | Bothrops jararaca Neuroprotection Bioactive peptide Proline-rich oligopeptide |
| url | http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1678-91992024000100302&tlng=en |
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