Effects of p38 MAPK signaling pathway on cognitive function and recovery of neuronal function after hypoxic-ischemic brain injury in newborn rats

Abstract

To explore the effects of p38 MAPK signaling pathway on cognitive function and recovery of neuronal function after hypoxic-ischemic brain injury (HIBI) in newborn rats. Seventy-two healthy SPF grade SD newborn rats were randomly and equally divided into Normal group (healthy rats) and Sham group (rats underwent sham operation), Model group (HIBI model rats), p38 MAPK Inhibitor group (HIBI model rats treated with p38 MAPK inhibitor) and p38 MAPK Activator group (HIBI model rats treated with p38 MAPK activator). On postnatal day 28, Morris water maze, tail suspension test and inclined plane test were conducted on rats in each group. Twenty-four hours after modeling, the expression of p-p38 MAPK protein and apoptosis related genes in rat hippocampal tissues was detected by TUNEL staining, qRT-PCR and Western blot. Compared with Normal group, escape latency and inclined plane test time were prolonged, the number of passing through the platform and tail suspension time were reduced (all P < 0.05); Bax and Caspase-3 mRNA and protein expression levels and p-p38 MAPK protein level were increased, Bcl-2 mRNA level was decreased, and neuronal apoptosis proportion was increased in Model group (all P < 0.05). Compared with Model group, the above indicators showed reversed and enhanced trends in p38 MAPK Inhibitor and p38 MAPK Activator groups, respectively (all P < 0.05). Inhibition of p38 MAPK signaling pathway can effectively improve the learning and memory ability and motor function of newborn rats with HIBI, and reduce neuronal apoptosis in the hippocampal tissues, thereby promoting neuronal recovery.

Prenatal Hyperhomocysteinemia Induces Glial Activation and Alters Neuroinflammatory Marker Expression in Infant Rat Hippocampus

“…Elevated expressions of inflammatory molecules may combine to have a contributing negative effect on neurons in the postnatal hippocampus. Several studies have shown that p38 MAPK phosphorylation increased in the hippocampus and the brain cortex under hypoxic conditions [ 57 ], and this p38 MAPK activation coincided with neuronal apoptosis and cognitive function deficit in young rats [ 58 ]. Central nervous system proinflammatory cytokine overproduction and release activated by p38 MAPK have been reported to promote neuronal damage [ 59 , 60 ].…”

Knockdown of PAR2 alleviates cancer-induced bone pain by inhibiting the activation of astrocytes and the ERK pathway

“…The model rats were randomly assigned to 9 groups using the random number table method including sham group ( N = 12), CIBP group (TCI) ( N = 36), CIBP + PAR-2 inhibitor group (TCI + PI group) ( N = 6), CIBP + normal saline group (TCI + N group) ( N = 6), CIBP + PAR-2 control peptide group (TCI + PJ group) ( N = 6), CIBP + PAR-2 inhibitor + ERK activator group (TCI +PI + EA group) ( N = 6), CIBP + PAR-2 inhibitor + dimethyl sulfoxide (DMSO) group (TCI + PI + N) ( N = 6), CIBP + PAR-2 inhibitor + ERK activator + CREB inhibitor group (TCI + PI + EA + CI) ( N = 6), and CIBP + PAR-2 inhibitor + ERK activator + DMSO group (TCI + PI + EA + N) ( N = 6). The model rats were intrathecally injected with 10 µL PAR-2 inhibitor FSLLRY-NH2 (1 mmol/L, FSLLRY-NH2, CAS No.245329-02-6, MedChemExpress, Monmouth Junction, NJ, USA) [ 15 ], PAR-2 control peptide (LRGISL-NH2, Bachem Inc., Torrance, CA, USA), 10 µL ERK activator Dehydrocorydaline chloride (10 mg/kg, HY-N0674A, MedChemExpress) [ 16 ] and 10 µL CREB inhibitor KG-501 (70,485, Sigma-Aldrich, St. Louis, MO, USA) on the 13th d after the operation. The equivalent volume of normal saline (1 mmol/L) and DMSO were set as the corresponding controls.…”

The Role of Formyl Peptide Receptors in Neurological Diseases via Regulating Inflammation

“…Thereafter, pro-inflammatory cytokines (TNF-α and IL-1β) promote neuronal apoptosis and necrosis, thus impairing neurological functions and inhibiting neurogenesis, which leads to secondary brain tissue injury ( Ziemka-Nalecz et al, 2017 ). Activation of the p38/MAPK signaling pathway inhibits the learning, memory, and motor function of newborn rats with hypoxic-ischemic brain injury and promotes neuronal apoptosis in the hippocampal tissues ( Zhu et al, 2020 ). A recent study found that FPRs play an important role in HIE.…”

“…A recent study found that FPRs play an important role in HIE. Activation of FPR2 with RvD1-attenuated neuroinflammation interacted with the Rac1/NOX2 signaling pathway, causing a decrease in the infarcted region and alleviating neurological deficits after HIE ( Zhu et al, 2020 ). After hypoxic-ischemic injury, excessive glutamate release, free radical production, and an increase in BBB-permeability occur due to energy failure ( Moretti et al, 2015 ).…”