Perinatal asphyxia results in altered expression of the hippocampal acylethanolamide/endocannabinoid signaling system associated to memory impairments in postweaned rats

Abstract

Perinatal asphyxia (PA) is an obstetric complication that strongly affects the CNS. The endocannabinoid system (ECS) is a lipid transmitter system involved in several physiological processes including synaptic plasticity, neurogenesis, memory, and mood. Endocannabinoids, and other acylethanolamides (AEs) without endocannabinoid activity, have recently received growing attention due to their potential neuroprotective functions in neurological disorders, including cerebral ischemia. In the present study, we aimed to analyze the changes produced by PA in the major metabolic enzymes and receptors of the ECS/AEs in the hippocampus using a rodent model of PA. To induce PA, we removed uterine horns from ready-to-deliver rats and immersed them into a water bath during 19 min. Animals delivered spontaneously or by cesarean section were employed as controls. At 1 month of age, cognitive functions were assessed and immunohistochemical procedures were carried out to determine the expression of NeuN and glial fibrillary acidic protein, enzymes responsible for synthesis (DAGLα and NAPE-PLD) and degradation (FAAH) of ECS/AEs and their receptors (CB1 and PPARα) in the hippocampus. Postweaned asphyctic rats showed impaired recognition and spatial reference memory that were accompanied by hippocampal astrogliosis and changes in the expression of enzymes and receptors. The most remarkable findings in asphyctic rats were a decrease in the expression of NAPE-PLD and PPARα in both hippocampal areas CA1 and CA3. In addition, postweaned cesarean delivery rats showed an increase in the immunolabeling for FAAH in the hippocampal CA3 area. Since, NAPE-PLD and PPARα are proteins that participate in the biochemical process of AEs, specially the neuroprotective oleoylethanolamide, these results suggest that PA dysregulates this system. These data encourage conducting future studies using AEs as potential neuroprotective compounds in animal models of PA.

Partial Reversal of Striatal Damage by Palmitoylethanolamide Administration Following Perinatal Asphyxia

“…Recently, we reported that PEA neuroprotected from dendritic and axonal cytoskeletal alterations induced by PA in the hippocampus (Herrera et al, 2018). Interestingly, Blanco et al (2015) showed that PA induced a substantial decrease in the protein level of the PEA receptor, PPARα, and in N-acyl phosphatidylethanolamine-specific phospholipase D (Blanco et al, 2015), an enzyme that synthesizes acylethanolamides like PEA (Harrison et al, 2014) also at P30. This reduction could lead to dysregulation and a decrease in endocannabinoids level, inhibiting PPARα activity (Blanco et al, 2015).…”

“…Interestingly, Blanco et al (2015) showed that PA induced a substantial decrease in the protein level of the PEA receptor, PPARα, and in N-acyl phosphatidylethanolamine-specific phospholipase D (Blanco et al, 2015), an enzyme that synthesizes acylethanolamides like PEA (Harrison et al, 2014) also at P30. This reduction could lead to dysregulation and a decrease in endocannabinoids level, inhibiting PPARα activity (Blanco et al, 2015). Then, reasonably enough, the exogenous administration of PEA may be responsible for the protective effects reported in this study.…”

“…Fifty-three male rat pups were subjected to PA using an experimental model (Bjelke et al, 1991), which produces moderate to severe PA (Van de Berg et al, 2003;Galeano et al, 2011) as we described previously (Capani et al, 2003(Capani et al, , 2009Saraceno et al, 2010Saraceno et al, , 2012aBlanco et al, 2015;Holubiec et al, 2017;Herrera et al, 2018). The murine model of PA, originally developed by Bjelke et al (1991), has been widely used (Barkhuizen et al, 2017;Herrera et al, 2017b) and accepted to mimic this condition (Capani et al, 1997(Capani et al, , 2003(Capani et al, , 2009Boksa and El-Khodor, 2003;Saraceno et al, 2010Saraceno et al, , 2012aStrackx et al, 2010;Muñiz et al, 2014;Romero et al, 2015;Wakuda et al, 2015;Herrera et al, 2018).…”

“…After weaning, rats were housed in cages of three to four animals from the same group. Cesarean controls were not used since previous studies revealed that this group did not present significant differences with vaginal controls (Galeano et al, 2011;Blanco et al, 2015). The selection of male animals is supported by the fact that estrogens exert neuroprotective properties (Saraceno et al, 2010).…”

“…One month after a severe, 20-min PA, the rats developed an alteration in the endocannabinoid system expression and related acylethanolamide pathways (Blanco et al, 2015). Palmitoylethanolamide (PEA) is an endogenous lipidic neuromodulator related to endocannabinoids, acting as a peroxisome proliferator-activated receptor alpha (PPARα) or G protein-coupled receptor 55 (GPR55) agonist that elicits anti-inflammatory, neuroprotective, and restorative properties (Mattace Raso et al, 2014;Petrosino and Di Marzo, 2017) in vitro (Avagliano et al, 2016), in animal models of both neurodegeneration (Esposito et al, 2011(Esposito et al, , 2012(Esposito et al, , 2014Herrera et al, 2016) and hypoxia-ischemia (HI) (Fernandez-Lopez et al, 2013;England et al, 2015), and in human patients as well (Orefice et al, 2016).…”