THE PREVENTIVE EFFECTS OF ULTRA-MICRONIZED PALMITOYLETHANOLAMIDE (PEA) IN A PRECLINICAL MODEL OF SCHIZOPHRENIA

Abstract Background Schizophrenia (SCZ) is a complex neurodevelopmental disorder with an early adult-onset, typically following multiple pathogenic factors, including neuroinflammatory events1. Current antipsychotics are insufficient at treating the full range of symptoms, posing the need for novel therapies. To date, the maternal immune activation (MIA) model has both high face and predictive validities, making it the most translatable model for preclinical work. The endocannabinoid (ECB) system is a target for novel interventions due to its role in neurodevelopment and regulating inflammatory processes; however, targeting the main brain cannabinoid receptor, CB1R, has proven ineffective2. Brain- wide CB2Rs are a novel target for SCZ treatment and prevention as they are known to regulate inflammatory processes that contribute to its pathology. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide that binds to PPAR-alpha receptors to indirectly activate CB2R, triggering an anti- inflammatory cascade, regulating neuroinflammation3,4. Aims & Objectives This study investigates the potential protective effects of PEA and associated CB2 and PPAR-alpha-mediated mechanisms. We hypothesize that maternal lipopolysaccharide (LPS) exposure will induce juvenile behavioural deficits and mismatch negativity (MMN)5,6, and PEA administration prior to onset of adolescence will mitigate or block these deficits. Additionally, adolescent PEA treatment will result in the prevention of impaired ECB signaling, resulting in control levels of endogenous ECBs and proinflammatory cytokines. Method This project uses a mouse MIA model combined with stress activation during adolescence and detailed behavioural and brain analyses to investigate the effects of PEA. Prior to MIA, we used an acute MK-801 model to test whether oral PEA pretreatment in adult mice would prevent MK-801-induced deficits in auditory MMN measured by EEG. Brains were collected from dams following weaning and at three different time points for offspring: postnatal day (PND) 0, 20, and 70. Extracted brains will be used for ELISA cytokines analysis, mass spectroscopy measurement of ECB and endogenous PEA levels, and epigenetic analysis of genes encoding for CB2R, CB1R, and PPAR-alpha. Results PEA pretreatment prevented MK-801-induced MMN deficits in both male and female adult mice (p = 0.02). Offspring from dams administered LPS on gestation day 14.5 mice presented with social deficits (p = 0.02) and novel object recognition impairments (p = 0.03); meanwhile, PEA prevented these deficits, restoring behaviors to healthy control levels (p = 0.01). Female LPS-PEA mice displayed healthy control novel object recognition behavior (p = 0.02); however, did not prevent social deficits in LPS females (p >0.05). Preliminary EEG-MMN analysis indicates PEA prevented MMN deficits in adult MIA offpsring. Analysis of extracted brains is currently underway. Discussion & Conclusion SCZ is a debilitating mental illness that does not manifest its symptoms until late adolescence. With the identification of CHR youth, the importance of developing safe and effective preventive interventions is evident. This study has thus far provided promising data indicating SCZ typical behaviors in MK-801 and MIA mouse models can be prevented with oral PEA pretreatment. The outcome of this study could direct future research towards the discovery of safe and effective preventive interventions for SCZ. References [1]Arsenault, D., St-Amour, I., Cisbani, G., Rousseau, L. S., &Cicchetti, F. (2014). The different effects of LPS and poly I:C prenatal immune challenges on the behavior, development and inflammatory responses in pregnant mice and their offspring. Brain, Behaviour, and Immunity, 38(1), 77-90. [2]Malek, N., Popiolek-Barczyk, K., Mika, J., Przewlocka, B., &Starowicz, K. (2015). Anandamide, acting via CB2 receptors, alleviates LPS-induced neuroinflammation in rat primary microglial cultures. Neural Plasticity, 1-10. [3]Borrelli, F., Romano, B., Petrosino, S., Pagano, E., Capasso, R., Coppola, D., Battista, G., Orlando, P., Di Marzo, V., &Izzo, A. (2015). Palmitoylethanolamide, a naturally occurring lipid, is an orally effective intestinal anti-inflammatory agent. British Journal of Pharmacology, 172(1), 142-158. [4]Missault, S., Van den Eynde, K., Vanden Berghe, W., Fransen, E., Weeren, A., Timmermans, J. P., Kumar- Singh, S., &Dedeurwaerdere, S. (2014). The risk for behavioural deficits is determined by the maternal immune response to prenatal immune challenge in a neurodevelopmental model. Brain, Behaviour, and Immunity, 42(1), 138-146. [5]Nagai, T., Tada, M., Kirihara, K., Araki, T., Jinde, S., &Kasai, K. (2013). Mismatch negativity as a “translatable” brain marker toward early intervention for psychosis: a review. Frontiers in Psychiatry, 115(4), 1-10. [6]Tada, M., Kirihara, K., Mizutani, S., Uka, T., Kunii, N., Koshiyama, D., Fujioka, M., Usi, K., Nagai, T., Araki, T., &Kasai, K. (2019). Mismatch negativity (MMN) as a tool for translational investigations into early psychosis: a review. International Journal of Psychophysiology, 145(1), 5-14.

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