Partial Reversal of Striatal Damage by Palmitoylethanolamide Administration Following Perinatal Asphyxia

Abstract

Perinatal asphyxia (PA) is a clinical condition brought by a birth temporary oxygen deprivation associated with long-term damage in the corpus striatum, one of the most compromised brain areas. Palmitoylethanolamide (PEA) is a neuromodulator well known for its protective effects in brain injury models, including PA, albeit not deeply studied regarding its particular effects in the corpus striatum following PA. Using Bjelke et al. (1991) PA model, full-term pregnant rats were decapitated, and uterus horns were placed in a water bath at 37 • C for 19 min. One hour later, the pups were injected with PEA 10 mg/kg s.c., and placed with surrogate mothers. After 30 days, the animals were perfused, and coronal striatal sections were collected to analyze protein-level expression by Western blot and the reactive area by immunohistochemistry for neuron markers: phosphorylated neurofilament-heavy/medium-chain (pNF-H/M) and microtubule-associated protein-2 (MAP-2), and the astrocyte marker, glial fibrillary acidic protein (GFAP). Results indicated that PA produced neuronal damage and morphological changes. Asphyctic rats showed a decrease in pNF-H/M and MAP-2 reactive areas, GFAP + cells number, and MAP-2 as well as pNF-H/M protein expression in the striatum. Treatment with PEA largely restored the number of GFAP + cells. Most important, it ameliorated the decrease in pNF-H/M and MAP-2 reactive areas in asphyctic rats. Noticeably, PEA treatment reversed the decrease in MAP-2 protein expression and largely prevented PA-induced decrease in pNF-H/M protein expression. PA did not affect the GFAP protein level. Treatment with PEA attenuated striatal damage induced by PA, suggesting its therapeutic potential for the prevention of neurodevelopmental disorders.

Synaptoprotection in Perinatal Asphyxia: An Experimental Approach

“…Recent evidence from our laboratory revealed that PA resulted in a short-term reduction in microtubule-associated protein 2 (MAP-2) immunostaining in the CA1 hippocampal area (Herrera et al, 2018) and the corpus striatum (Udovin et al, 2020), as was found at P30. Protein expression analysis by Western blot confirmed this dendritic alteration.…”

“…decrease in MAP-2 and pNF-H/M reactive areas, reversed the decrease in MAP-2 expression, and prevented pNF-H/M depletion Udovin et al (2020). …”

“…Protein expression analysis by Western blot confirmed this dendritic alteration. Moreover, immunohistochemistry and Western blot showed deregulation of axonal phosphorylated high- and medium-molecular-weight neurofilament chains (pNF-H/M) in the hippocampus (Herrera et al, 2018 ) and the corpus striatum (Udovin et al, 2020 ) 1 month after PA. The changes in the respective dendritic and axonal markers were correlated with decreased vertical exploration and alterations in anxiety levels, inferred from prototypical behaviors in animals like rearing and grooming (Herrera et al, 2018 ).…”

“…Ethanolamine and palmitic acid react, giving rise to palmitoylethanolamide (PEA), a lipid compound that has shown protective effects after PA. Treatment with PEA (10 mg/kg) within the first hour of life reduced dendritic MAP-2 level and led to the deregulation of pNF-H/M axonal level in the CA1 hippocampal area (Herrera et al, 2018 ) and the corpus striatum (Udovin et al, 2020 ) 1 month after PA ( Table 1 ). The morphological and biochemical neuroprotective effects in CA1 were associated with the improved exploratory activity and anxiety mitigation at P30.…”

“…This theoretical perspective, traced in the context of Alzheimer’s disease (Coleman et al, 2004 ), offers an interesting viewpoint for the progressive neurological dysfunction originating early in life (Marriott et al, 2017 ) following PA. Synaptoprotective treatments in PA neonates should target short-term markers preceding chronic signs of neurodegeneration (Capani et al, 2009 ; Saraceno et al, 2012b ). The focus should be on protein damage (Grimaldi et al, 2012 ) in F-actin (Saraceno et al, 2012a , 2016 ), MAP-2 and pNF-H/M (Herrera et al, 2018 ; Udovin et al, 2020 ), reductions in neurite length and branching, and decreases in synaptophysin and PSD95 levels (Rojas-Mancilla et al, 2013 ) found 1 month after PA. Earlier indicators of PA-induced synaptic disorganization, like the change in NGF and BDNF contents in the first weeks of life, are also relevant.…”