Modulation of Kynurenic Acid Production by N-acetylcysteine Prevents Cognitive Impairment in Adulthood Induced by Lead Exposure during Lactation in Mice
Paulina Ovalle Rodríguez,
Daniela Ramírez Ortega,
Tonali Blanco Ayala,
Gabriel Roldán Roldán,
Gonzalo Pérez de la Cruz,
Dinora Fabiola González Esquivel,
Saúl Gómez-Manzo,
Laura Sánchez Chapul,
Aleli Salazar,
Benjamín Pineda,
Verónica Pérez de la Cruz
Affiliations
Paulina Ovalle Rodríguez
Neurochemistry and Behavior Laboratory, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Mexico City 14269, Mexico
Daniela Ramírez Ortega
Neurochemistry and Behavior Laboratory, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Mexico City 14269, Mexico
Tonali Blanco Ayala
Neurochemistry and Behavior Laboratory, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Mexico City 14269, Mexico
Gabriel Roldán Roldán
Laboratorio de Neurobiología de la Conducta, Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
Gonzalo Pérez de la Cruz
Department of Mathematics, Faculty of Sciences, Universidad Nacional Autónoma de México UNAM, Mexico City 04510, Mexico
Dinora Fabiola González Esquivel
Neurochemistry and Behavior Laboratory, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Mexico City 14269, Mexico
Saúl Gómez-Manzo
Laboratorio de Bioquímica Genética, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City 04530, Mexico
Laura Sánchez Chapul
Neuromuscular Diseases Laboratory, Clinical Neurosciences Division, National Institute of Rehabilitation “Luis Guillermo Ibarra Ibarra”, Mexico City 14389, Mexico
Aleli Salazar
Neuroimmunology Department, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Mexico City 14269, Mexico
Benjamín Pineda
Neuroimmunology Department, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Mexico City 14269, Mexico
Verónica Pérez de la Cruz
Neurochemistry and Behavior Laboratory, National Institute of Neurology and Neurosurgery “Manuel Velasco Suárez”, Mexico City 14269, Mexico
Lead (Pb2+) exposure during early life induces cognitive impairment, which was recently associated with an increase in brain kynurenic acid (KYNA), an antagonist of NMDA and alpha-7 nicotinic receptors. It has been described that N-acetylcysteine (NAC) favors an antioxidant environment and inhibits kynurenine aminotransferase II activity (KAT II, the main enzyme of KYNA production), leading to brain KYNA levels decrease and cognitive improvement. This study aimed to investigate whether the NAC modulation of the brain KYNA levels in mice ameliorated Pb2+-induced cognitive impairment. The dams were divided into four groups: Control, Pb2+, NAC, and Pb2++NAC, which were given drinking water or 500 ppm lead acetate in the drinking water ad libitum, from 0 to 23 postnatal days (PNDs). The NAC and Pb2++NAC groups were simultaneously fed NAC (350 mg/day) in their chow from 0 to 23 PNDs. At PND 60, the effect of the treatment with Pb2+ and in combination with NAC on learning and memory performance was evaluated. Immediately after behavioral evaluation, brain tissues were collected to assess the redox environment; KYNA and glutamate levels; and KAT II activity. The NAC treatment prevented the long-term memory deficit exhibited in the Pb2+ group. As expected, Pb2+ group showed redox environment alterations, fluctuations in glutamate levels, and an increase in KYNA levels, which were partially avoided by NAC co-administration. These results confirmed that the excessive KYNA levels induced by Pb2+ were involved in the onset of cognitive impairment and could be successfully prevented by NAC treatment. NAC could be a tool for testing in scenarios in which KYNA levels are associated with the induction of cognitive impairment.
