title: Preventive effect of α-lipoic acid on prepulse inhibition deficits in a juvenile two-hit model of schizophrenia.
abstract: Some pathophysiological models of schizophrenia posit that prenatal inflammation sensitizes the developing brain to second insults in early life and enhances brain vulnerability, thereby increasing the risk of developing the disorder during adulthood. We previously developed a two-hit animal model, based on the well-established prenatal immune challenge with poly-inosinic/cytidylic acid (polyI:C), followed by juvenile restraint stress (RS). We observed an additive disruption of prepulse inhibition (PPI) of acoustic startle in juvenile mice submitted to both insults. Previous studies have also reported that oxidative stress is associated with pathophysiological mechanisms of psychiatric disorders, including schizophrenia. We report here that PPI disruption in our two-hit animal model of schizophrenia is associated with an increase in oxidative stress. These findings led us to assess whether α-lipoic acid, an antioxidant, can prevent both increase in oxidative status and PPI deficits in our juvenile in vivo model of schizophrenia. In the offspring submitted to prenatal injection of polyI:C and to RS, treatment with α-lipoic acid prevented the development of PPI deficits 24h after the last period of RS. α-Lipoic acid also improved PPI performance in control mice. The reversal effect of α-lipoic acid pretreatment on these behavioral alterations was further accompanied by a normalization of the associated oxidative status and dopaminergic and GABAergic abnormalities in the prefrontal cortex. Based on our double insult paradigm, these results support the hypothesis that oxidative stress plays an important role in the development of PPI deficits, a well-known behavior associated with schizophrenia. These findings form the basis of future studies aiming to unravel mechanistic insights of the putative role of antioxidants in the treatment of schizophrenia, especially during the prodromal stage.
authors.affiliation: Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 12(e) avenue Nord, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Deslauriers
authors.affiliation: Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 12(e) avenue Nord, Sherbrooke, QC J1H 5N4, Canada; Department of Psychiatry, Centre Hospitalier Universitaire de Sherbrooke, 580 Bowen Sud, Sherbrooke, QC J1G 2E8, Canada.
authors.forename: W
authors.initials: W
authors.lastname: Racine
authors.affiliation: Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 12(e) avenue Nord, Sherbrooke, QC J1H 5N4, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Sarret
authors.affiliation: Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 12(e) avenue Nord, Sherbrooke, QC J1H 5N4, Canada; Department of Psychiatry, Centre Hospitalier Universitaire de Sherbrooke, 580 Bowen Sud, Sherbrooke, QC J1G 2E8, Canada. Electronic address: Sylvain.Grignon@USherbrooke.ca.
authors.forename: S
authors.initials: S
authors.lastname: Grignon
mesh_terms: D000375:Aging; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D008297:Male; D008810:Mice, Inbred C57BL; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000503:physiopathology; D011247:Pregnancy; D011954:Receptors, Dopamine / Q000187:drug effects*; D013216:Reflex, Startle / Q000187:drug effects*; D012559:Schizophrenia / Q000188:drug therapy*; D008063:Thioctic Acid / Q000494:pharmacology*
chemical_list: D011954:Receptors, Dopamine; D008063:Thioctic Acid
keywords: GAD67; dopamine D2 receptor; lipoic acid; prepulse inhibition; schizophrenia