The PPARα Agonist Fenofibrate Attenuates Disruption of Dopamine Function in a Maternal Immune Activation Rat Model of Schizophrenia

Overview

Journal CNS Neurosci Ther

Specialties Neurology
Pharmacology

Date 2018 Nov 22

PMID 30461214

Citations 20

Authors

Marta De Felice

Miriam Melis

Sonia Aroni

Anna Lisa Muntoni

Silvia Fanni

Roberto Frau

Paola Devoto

Marco Pistis

Affiliations

Soon will be listed here.

Abstract

Aims: Prenatal maternal immune activation (MIA) is associated with a risk to develop schizophrenia and affects dopamine systems in the ventral tegmental area (VTA), key region in the neurobiology of psychoses. Considering the well-described sex differences in schizophrenia, we investigated whether sex affects MIA impact on dopamine system and on schizophrenia-related behavioral phenotype. Furthermore, considering peroxisome proliferator-activated receptor-α (PPARα) expression in the CNS as well as its anti-inflammatory and neuroprotective properties, we tested if PPARα activation by prenatal treatment with a clinically available fibrate (fenofibrate) may mitigate MIA-related effects.

Methods: We induced MIA in rat dams with polyriboinosinic-polyribocytidylic acid (Poly I:C) and assessed prepulse inhibition and dopamine neuron activity in the VTA by means of electrophysiological recordings in male and female preweaned and adult offspring.

Results: Poly I:C-treated males displayed prepulse inhibition deficits, reduced number and firing rate of VTA dopamine neurons, and paired-pulse facilitation of inhibitory and excitatory synapses. Prenatal fenofibrate administration attenuated detrimental effects induced by MIA on both the schizophrenia-like behavioral phenotype and dopamine transmission in male offspring.

Conclusion: Our study confirms previous evidence that females are less susceptible to MIA and highlights PPARα as a potential target for treatments in schizophrenia.

Citing Articles

Pioglitazone attenuates behavioral and electrophysiological dysfunctions induced by two-hit model of schizophrenia in adult rodent offspring.

Sonego A, Prado D, Uliana D, Cunha T, Grace A, Resstel L Eur Neuropsychopharmacol. 2024; 89:28-40.

PMID: 39332147 PMC: 11606766. DOI: 10.1016/j.euroneuro.2024.09.001.

Current View on PPAR-α and Its Relation to Neurosteroids in Alzheimer's Disease and Other Neuropsychiatric Disorders: Promising Targets in a Therapeutic Strategy.

Zulinska S, Strosznajder A, Strosznajder J Int J Mol Sci. 2024; 25(13).

PMID: 39000217 PMC: 11241121. DOI: 10.3390/ijms25137106.

Maternal Immune Activation Induces Cortical Catecholaminergic Hypofunction and Cognitive Impairments in Offspring.

Perez-Palomar B, Erdozain A, Erkizia-Santamaria I, Ortega J, Meana J J Neuroimmune Pharmacol. 2023; 18(3):348-365.

PMID: 37208550 PMC: 10577104. DOI: 10.1007/s11481-023-10070-1.

Connecting Neurobiological Features with Interregional Dysconnectivity in Social-Cognitive Impairments of Schizophrenia.

Adraoui F, Douw L, Martens G, Maas D Int J Mol Sci. 2023; 24(9).

PMID: 37175387 PMC: 10177877. DOI: 10.3390/ijms24097680.

CTNNB1 in neurodevelopmental disorders.

Zhuang W, Ye T, Wang W, Song W, Tan T Front Psychiatry. 2023; 14:1143328.

PMID: 37009120 PMC: 10061110. DOI: 10.3389/fpsyt.2023.1143328.

References

Sunman H, Canpolat U, Sahiner L, Aytemir K . Use of fenofibrate during the first trimester of unplanned pregnancy in a patient with hypertriglyceridemia. Ann Pharmacother. 2012; 46(2):e5. DOI: 10.1345/aph.1Q626. View

Frau R, Bini V, Pes R, Pillolla G, Saba P, Devoto P . Inhibition of 17α-hydroxylase/C17,20 lyase reduces gating deficits consequent to dopaminergic activation. Psychoneuroendocrinology. 2013; 39:204-213. PMC: 3940882. DOI: 10.1016/j.psyneuen.2013.09.014. View

Kirsten T, Taricano M, Maiorka P, Palermo-Neto J, Bernardi M . Prenatal lipopolysaccharide reduces social behavior in male offspring. Neuroimmunomodulation. 2010; 17(4):240-51. DOI: 10.1159/000290040. View

Stewart J, Rajabi H . Estradiol derived from testosterone in prenatal life affects the development of catecholamine systems in the frontal cortex in the male rat. Brain Res. 1994; 646(1):157-60. DOI: 10.1016/0006-8993(94)90070-1. View

Luchicchi A, Lecca S, Melis M, De Felice M, Cadeddu F, Frau R . Maternal Immune Activation Disrupts Dopamine System in the Offspring. Int J Neuropsychopharmacol. 2016; 19(7). PMC: 4966272. DOI: 10.1093/ijnp/pyw007. View

Zhang Y, Cazakoff B, Thai C, Howland J . Prenatal exposure to a viral mimetic alters behavioural flexibility in male, but not female, rats. Neuropharmacology. 2011; 62(3):1299-307. PMC: 4457519. DOI: 10.1016/j.neuropharm.2011.02.022. View

Melis M, Carta G, Pistis M, Banni S . Physiological role of peroxisome proliferator-activated receptors type α on dopamine systems. CNS Neurol Disord Drug Targets. 2013; 12(1):70-7. DOI: 10.2174/1871527311312010012. View

Sakuma Y . Gonadal steroid action and brain sex differentiation in the rat. J Neuroendocrinol. 2009; 21(4):410-4. DOI: 10.1111/j.1365-2826.2009.01856.x. View

Howland J, Cazakoff B, Zhang Y . Altered object-in-place recognition memory, prepulse inhibition, and locomotor activity in the offspring of rats exposed to a viral mimetic during pregnancy. Neuroscience. 2011; 201:184-98. PMC: 4464820. DOI: 10.1016/j.neuroscience.2011.11.011. View

10.

Bitanihirwe B, Peleg-Raibstein D, Mouttet F, Feldon J, Meyer U . Late prenatal immune activation in mice leads to behavioral and neurochemical abnormalities relevant to the negative symptoms of schizophrenia. Neuropsychopharmacology. 2010; 35(12):2462-78. PMC: 3055332. DOI: 10.1038/npp.2010.129. View

11.

Jones D, Ding X, Daynes R . Nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) is expressed in resting murine lymphocytes. The PPARalpha in T and B lymphocytes is both transactivation and transrepression competent. J Biol Chem. 2001; 277(9):6838-45. DOI: 10.1074/jbc.M106908200. View

12.

Jiang B, Wang Y, Wang H, Song L, Huang C, Zhu Q . Antidepressant-like effects of fenofibrate in mice via the hippocampal brain-derived neurotrophic factor signalling pathway. Br J Pharmacol. 2016; 174(2):177-194. PMC: 5192965. DOI: 10.1111/bph.13668. View

13.

Weinstein J, Chohan M, Slifstein M, Kegeles L, Moore H, Abi-Dargham A . Pathway-Specific Dopamine Abnormalities in Schizophrenia. Biol Psychiatry. 2016; 81(1):31-42. PMC: 5177794. DOI: 10.1016/j.biopsych.2016.03.2104. View

14.

Hadar R, Soto-Montenegro M, Gotz T, Wieske F, Sohr R, Desco M . Using a maternal immune stimulation model of schizophrenia to study behavioral and neurobiological alterations over the developmental course. Schizophr Res. 2015; 166(1-3):238-47. PMC: 5233455. DOI: 10.1016/j.schres.2015.05.010. View

15.

Zuckerman L, Rehavi M, Nachman R, Weiner I . Immune activation during pregnancy in rats leads to a postpubertal emergence of disrupted latent inhibition, dopaminergic hyperfunction, and altered limbic morphology in the offspring: a novel neurodevelopmental model of schizophrenia. Neuropsychopharmacology. 2003; 28(10):1778-89. DOI: 10.1038/sj.npp.1300248. View

16.

Bonci A, Williams J . Increased probability of GABA release during withdrawal from morphine. J Neurosci. 1997; 17(2):796-803. PMC: 6573250. View

17.

Winter C, Djodari-Irani A, Sohr R, Morgenstern R, Feldon J, Juckel G . Prenatal immune activation leads to multiple changes in basal neurotransmitter levels in the adult brain: implications for brain disorders of neurodevelopmental origin such as schizophrenia. Int J Neuropsychopharmacol. 2008; 12(4):513-24. DOI: 10.1017/S1461145708009206. View

18.

Ujhazy E, Onderova E, Horakova M, Bencova E, Durisova M, Nosal R . Teratological study of the hypolipidaemic drugs etofylline clofibrate (VULM) and fenofibrate in Swiss mice. Pharmacol Toxicol. 1989; 64(3):286-90. DOI: 10.1111/j.1600-0773.1989.tb00648.x. View

19.

Swerdlow N, Braff D, Taaid N, Geyer M . Assessing the validity of an animal model of deficient sensorimotor gating in schizophrenic patients. Arch Gen Psychiatry. 1994; 51(2):139-54. DOI: 10.1001/archpsyc.1994.03950020063007. View

20.

Ovtscharoff W, Eusterschulte B, Zienecker R, Reisert I, Pilgrim C . Sex differences in densities of dopaminergic fibers and GABAergic neurons in the prenatal rat striatum. J Comp Neurol. 1992; 323(2):299-304. DOI: 10.1002/cne.903230212. View