Modulation of Brain Kynurenic Acid by N-Acetylcysteine Prevents Cognitive Impairment and Muscular Weakness Induced by Cisplatin in Female Rats
Cisplatin (CIS) is a potent chemotherapeutic agent primarily used to treat hematologic malignancies and solid tumors, including lymphomas, sarcomas, and some carcinomas. Patients receiving this treatment for tumors outside the nervous system develop cognitive impairment. Alterations in the kynurenin...
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| author | Teminijesu Dorcas Aremu Daniela Ramírez Ortega Tonali Blanco Ayala Dinora Fabiola González Esquivel Benjamín Pineda Gonzalo Pérez de la Cruz Alelí Salazar Itamar Flores Karla F. Meza-Sosa Laura Sánchez Chapul Edgar Rangel-López Saúl Gómez-Manzo Adrián Márquez Navarro Gabriel Roldán Roldán Verónica Pérez de la Cruz |
| author_facet | Teminijesu Dorcas Aremu Daniela Ramírez Ortega Tonali Blanco Ayala Dinora Fabiola González Esquivel Benjamín Pineda Gonzalo Pérez de la Cruz Alelí Salazar Itamar Flores Karla F. Meza-Sosa Laura Sánchez Chapul Edgar Rangel-López Saúl Gómez-Manzo Adrián Márquez Navarro Gabriel Roldán Roldán Verónica Pérez de la Cruz |
| author_sort | Teminijesu Dorcas Aremu |
| collection | DOAJ |
| description | Cisplatin (CIS) is a potent chemotherapeutic agent primarily used to treat hematologic malignancies and solid tumors, including lymphomas, sarcomas, and some carcinomas. Patients receiving this treatment for tumors outside the nervous system develop cognitive impairment. Alterations in the kynurenine pathway (KP) following CIS treatment suggest that certain KP metabolites may cross the blood–brain barrier, leading to increased production of the neuromodulator kynurenic acid (KYNA), which is associated with cognitive impairment. This study aimed to evaluate the effects of modulating brain KYNA levels by the administration of N-acetylcysteine (NAC), an inhibitor of kynurenine aminotransferase II (KATII), an enzyme responsible for KYNA biosynthesis on the cognitive and neuromuscular deficits induced by CIS. Female Wistar rats were divided into four groups: control, NAC (300 mg/day/8 days), CIS (3 mg/kg i.p/5 days), and NAC + CIS (both treatments co-administered in parallel). Seven days after the last CIS administration, cognitive performance, muscle strength, brain KYNA levels, KATII activity, and brain tissue redox profile (lipid peroxidation and oxidized/reduced glutathione (GSH/GSSG) ratio) were assessed. CIS did not affect short-term memory but induced long-term memory deficits and reduced muscle strength, effects which were prevented by NAC co-administration. CIS decreased the GSH/GSSG ratio and the number of cells in the brain cortex while it increased lipid peroxidation, KYNA levels, and marginal KATII activity. All these effects were attenuated by the co-administration of NAC. These findings suggest that NAC mitigates the side effects of CIS, such as chemo-brain and muscle weakness, by improving the redox imbalance and modulating KYNA levels by limiting its non-enzymatic production by reactive oxygen species (ROS). |
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| spelling | doaj-art-e1a4c5cf4fcd499b859e83102fbda4282024-12-13T16:24:14ZengMDPI AGCells2073-44092024-12-011323198910.3390/cells13231989Modulation of Brain Kynurenic Acid by N-Acetylcysteine Prevents Cognitive Impairment and Muscular Weakness Induced by Cisplatin in Female RatsTeminijesu Dorcas Aremu0Daniela Ramírez Ortega1Tonali Blanco Ayala2Dinora Fabiola González Esquivel3Benjamín Pineda4Gonzalo Pérez de la Cruz5Alelí Salazar6Itamar Flores7Karla F. Meza-Sosa8Laura Sánchez Chapul9Edgar Rangel-López10Saúl Gómez-Manzo11Adrián Márquez Navarro12Gabriel Roldán Roldán13Verónica Pérez de la Cruz14Doctorado en Ciencias Biológicas, Centro Tlaxcala Biología de la Conducta, Universidad Autónoma de Tlaxcala, Tlaxcala 90070, MexicoNeurochemistry and Behavior Laboratory, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Mexico City 14269, MexicoNeurochemistry and Behavior Laboratory, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Mexico City 14269, MexicoNeurochemistry and Behavior Laboratory, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Mexico City 14269, MexicoNeuroimmunology Laboratory, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Mexico City 14269, MexicoDepartment of Mathematics, Faculty of Sciences, Universidad Nacional Autónoma de México, Mexico City 04510, MexicoNeuroimmunology Laboratory, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Mexico City 14269, MexicoNeuroimmunology Laboratory, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Mexico City 14269, MexicoNeurochemistry and Behavior Laboratory, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Mexico City 14269, MexicoNeuromuscular Diseases Laboratory, National Institute of Rehabilitation “Luis Guillermo Ibarra Ibarra”, Mexico City 14389, MexicoCell Reprogramming Laboratory, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Mexico City 14269, MexicoLaboratorio de Bioquímica Genética, Instituto Nacional de Pediatría, Secretaría de Salud, México City 04530, MexicoNeuroimmunology Laboratory, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Mexico City 14269, MexicoDoctorado en Ciencias Biológicas, Centro Tlaxcala Biología de la Conducta, Universidad Autónoma de Tlaxcala, Tlaxcala 90070, MexicoNeurochemistry and Behavior Laboratory, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Mexico City 14269, MexicoCisplatin (CIS) is a potent chemotherapeutic agent primarily used to treat hematologic malignancies and solid tumors, including lymphomas, sarcomas, and some carcinomas. Patients receiving this treatment for tumors outside the nervous system develop cognitive impairment. Alterations in the kynurenine pathway (KP) following CIS treatment suggest that certain KP metabolites may cross the blood–brain barrier, leading to increased production of the neuromodulator kynurenic acid (KYNA), which is associated with cognitive impairment. This study aimed to evaluate the effects of modulating brain KYNA levels by the administration of N-acetylcysteine (NAC), an inhibitor of kynurenine aminotransferase II (KATII), an enzyme responsible for KYNA biosynthesis on the cognitive and neuromuscular deficits induced by CIS. Female Wistar rats were divided into four groups: control, NAC (300 mg/day/8 days), CIS (3 mg/kg i.p/5 days), and NAC + CIS (both treatments co-administered in parallel). Seven days after the last CIS administration, cognitive performance, muscle strength, brain KYNA levels, KATII activity, and brain tissue redox profile (lipid peroxidation and oxidized/reduced glutathione (GSH/GSSG) ratio) were assessed. CIS did not affect short-term memory but induced long-term memory deficits and reduced muscle strength, effects which were prevented by NAC co-administration. CIS decreased the GSH/GSSG ratio and the number of cells in the brain cortex while it increased lipid peroxidation, KYNA levels, and marginal KATII activity. All these effects were attenuated by the co-administration of NAC. These findings suggest that NAC mitigates the side effects of CIS, such as chemo-brain and muscle weakness, by improving the redox imbalance and modulating KYNA levels by limiting its non-enzymatic production by reactive oxygen species (ROS).https://www.mdpi.com/2073-4409/13/23/1989chemo-braincognitive impairmentkynurenic acidredox environment |
| spellingShingle | Teminijesu Dorcas Aremu Daniela Ramírez Ortega Tonali Blanco Ayala Dinora Fabiola González Esquivel Benjamín Pineda Gonzalo Pérez de la Cruz Alelí Salazar Itamar Flores Karla F. Meza-Sosa Laura Sánchez Chapul Edgar Rangel-López Saúl Gómez-Manzo Adrián Márquez Navarro Gabriel Roldán Roldán Verónica Pérez de la Cruz Modulation of Brain Kynurenic Acid by N-Acetylcysteine Prevents Cognitive Impairment and Muscular Weakness Induced by Cisplatin in Female Rats Cells chemo-brain cognitive impairment kynurenic acid redox environment |
| title | Modulation of Brain Kynurenic Acid by N-Acetylcysteine Prevents Cognitive Impairment and Muscular Weakness Induced by Cisplatin in Female Rats |
| title_full | Modulation of Brain Kynurenic Acid by N-Acetylcysteine Prevents Cognitive Impairment and Muscular Weakness Induced by Cisplatin in Female Rats |
| title_fullStr | Modulation of Brain Kynurenic Acid by N-Acetylcysteine Prevents Cognitive Impairment and Muscular Weakness Induced by Cisplatin in Female Rats |
| title_full_unstemmed | Modulation of Brain Kynurenic Acid by N-Acetylcysteine Prevents Cognitive Impairment and Muscular Weakness Induced by Cisplatin in Female Rats |
| title_short | Modulation of Brain Kynurenic Acid by N-Acetylcysteine Prevents Cognitive Impairment and Muscular Weakness Induced by Cisplatin in Female Rats |
| title_sort | modulation of brain kynurenic acid by n acetylcysteine prevents cognitive impairment and muscular weakness induced by cisplatin in female rats |
| topic | chemo-brain cognitive impairment kynurenic acid redox environment |
| url | https://www.mdpi.com/2073-4409/13/23/1989 |
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