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Myelination is a crucial process in the nervous system. This study aimed to evaluate the progression of myelin sheath development in different brain regions of neonatal rats at distinct developmental stages using Chemical Exchange Saturation Transfer (CEST) 7-T MRI. Male SD rats of different ages (3 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months) were selected for the study. Advanced in vivo MRI experiments were conducted using a 7-T MRI scanner. Custom MatLab scripts were employed to generate MR images and process the data. Myelin staining was used to assess myelin distribution in various brain regions. Statistical analysis was performed using repeated measures multivariate analysis of variance (MANOVA) and Spearman’s rank correlation. The progression of myelination was significantly different in different brain regions (F(5, 30) = 3.34, P < 0.05), with the corpus callosum showing an accelerated rate of myelination. Within the first month alone, there was an increase of 46.1% in myelination (t(35) = 2.29, P < 0.05). The hypothalamus and internal capsule exhibited a more gradual yet consistent increase in myelination over the two-month period, with increases of 47.1% (t(35) = 2.27, P < 0.05) and 39.8% (t(35) = 2.59, P < 0.05), respectively. A substantial positive correlation was found between the MRI-based and histological measurements of myelination (r = 0.31, P < 0.05). This study demonstrates the potential of CEST 7-T MRI as a non-invasive tool for assessing myelination progression and provides insights into the differential myelination rates across various brain regions during early development.

Necrotizing enterocolitis (NEC) is a life-threatening inflammatory disease of preterm infants, increasingly viewed as a cytokine-driven disorder of the immature intestine. We aimed to characterize local peritoneal concentrations of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α (TNF-α) in a standardized neonatal rat NEC model and relate them to histopathological injury. Seventy-four SPRD/Mol/Lodz rat pups were allocated to a control group (CTRL; n = 12) or subjected to a hypoxia-hypothermia-formula-feeding NEC protocol (NEC; n = 62). After 72 h, small-intestinal samples were scored using a four-tier NEC scale (0–3), and peritoneal fluid cytokine levels were measured by ELISA. All CTRL animals exhibited normal histology (grade 0), whereas NEC pups showed a wide spectrum of lesions, with 66.6% classified as grade 2–3 and a significantly higher mean NEC score in NEC than CTRL (p < 0.001). Peritoneal IL-1β and TNF-α concentrations were markedly elevated in NEC versus CTRL animals (both p < 0.001), while IL-6 levels showed no statistically significant between-group difference. These findings indicate that experimental NEC in this model is accompanied by a pronounced local pro-inflammatory response dominated by IL-1β and TNF-α, whereas IL-6 may follow distinct temporal or compartment-specific kinetics. Peritoneal cytokine profiling may help refine mechanistic understanding and guide future biomarker and immunomodulatory strategies in NEC.

Prenatal alcohol exposure disrupts the development of normal fetal respiratory function, but whether it perturbs respiratory rhythmical discharge activity is unclear. Furthermore, it is unknown whether the 5-hydroxytryptamine 2A receptor (5-HT2AR) is involved in the effects of prenatal alcohol exposure. In the present study, pregnant female rats received drinking water containing alcohol at concentrations of 0%, 1%, 2%, 4%, 8% or 10% (v/v) throughout the gestation period. Slices of the medulla from 2-day-old neonatal rats were obtained to record respiratory rhythmical discharge activity. 5-HT2AR protein and mRNA levels in the pre-Bötzinger complex of the respiratory center were measured by western blot analysis and quantitative RT-PCR, respectively. Compared with the 0% alcohol group, respiratory rhythmical discharge activity in medullary slices in the 4%, 8% and 10% alcohol groups was decreased, and the reduction was greatest in the 8% alcohol group. Respiratory rhythmical discharge activity in the 10% alcohol group was irregular. Thus, 8% was the most effective alcohol concentration at attenuating respiratory rhythmical discharge activity. These findings suggest that prenatal alcohol exposure attenuates respiratory rhythmical discharge activity in neonatal rats by downregulating 5-HT2AR protein and mRNA levels.

L-DOPA triggers a dose-dependent increase in locomotor activity in newborn rats suspended in the air (air-stepping). Here, we report the effects of L-DOPA injection on the tissue level of monoamines and metabolites in different regions of the central nervous system (CNS) of postnatal day 5 pups. We also established correlations between some of our neurochemical measurements and basic locomotor parameters. L-DOPA (25–100 mg/kg) enhanced its tissue levels in the spinal cord, cortex, striatum, and brainstem regions. It induced a strong increase in the levels of the L-DOPA, dopamine, and their metabolites but had low effects on noradrenaline and serotonin across CNS regions. Of note, we also detected the tyramine derivative octopamine in the spinal cord. The inter-regional pattern of correlations between monoamine content showed an almost full metabolic connectivity for dopamine only when all L-DOPA conditions were pooled, and it revealed restricted connectivity for noradrenaline and serotonin in the spinal cord and the mesencephalic locomotor region. Locomotor parameters (quadrupedal locomotion and step numbers) correlated with the levels of L-DOPA and DA in restricted CNS regions at variance with noradrenaline and serotonin. Altogether, our data extend the idea that the neurochemical effect of L-DOPA is widespread and heterogeneous in the CNS, with prominent biochemical changes notably present in the spinal cord and M1 cortex, to the newborn rat.

The Notch signaling pathway plays an important role in the regulation of neurogenesis. The objective of this study was to investigate whether the Notch signaling pathway was involved in the neurogenesis impairment and long-term neurocognitive dysfunction caused by neonatal exposure to ketamine. On postnatal day 7 (PND-7), male Sprague–Dawley (SD) rats were intraperitoneally injected with 40 mg/kg ketamine four consecutive times (40 mg/kg × 4) at 1-h intervals. Notch ligand Jagged1 (0.5 mg/kg) and lentivirus overexpressing the Notch1 intracellular domain (LV-NICD1) were microinjected into the hippocampal dentate gyrus (DG) 1 h or 4 days before ketamine administration, respectively. The expression of Notch1 signaling pathway-related proteins was detected by Western blotting 24 h after ketamine administration. The proliferation and differentiation of the neural stem cells (NSCs) in the hippocampal DG were evaluated by double immunofluorescence staining 24 h after treatment. Moreover, changes in hippocampus-dependent spatial memory of 2-month-old rats were investigated with the Morris water maze test. Ketamine anesthesia in neonatal rats decreased the expression levels of Jagged1, Notch1, NICD1, and hairy enhancer of split 1 (Hes1); inhibited the proliferation and astrocytic differentiation of NSCs; and promoted the differentiation of neurons. Neonatal exposure to ketamine caused deficits in hippocampus-dependent spatial reference memory tasks in 2-month-old rats. Microinjection of Jagged1 or LV-NICD1 reversed the inhibitory effect of ketamine on the expression of Notch1-related proteins in the hippocampal DG, attenuated the ketamine-mediated decrease in NSC proliferation and differentiation, and improved the cognitive function of 2-month-old rats after neonatal exposure to ketamine. These results suggest that neonatal exposure to ketamine in rats inhibits the proliferation and differentiation of hippocampal NSCs and impairs neurocognitive function in adulthood. The Notch1 signaling pathway may be involved in the impairment of hippocampus-dependent learning and memory during adulthood caused by neonatal exposure to ketamine. These findings contribute to further understanding the neurotoxicity induced by neonatal exposure to ketamine and the underlying mechanisms.

Ketamine is an ionic glutamic acid N -methyl-d-aspartate receptor (NMDAR) antagonist commonly used in clinical anesthesia, and its rapid and lasting antidepressant effect has stimulated great interest in psychology research. However, the molecular mechanisms underlying its antidepressant action are still undetermined. Sevoflurane exposure early in life might induce developmental neurotoxicity and mood disorders. In this study, we evaluated the effect of ketamine against sevoflurane-induced depressive-like behavior and the underlying molecular mechanisms. Here, we reported that A2AR protein expression was upregulated in rats with depression induced by sevoflurane inhalation, which was reversed by ketamine. Pharmacological experiments showed that A2AR agonists could reverse the antidepressant effect of ketamine, decrease extracellular signal-regulated kinase (ERK) phosphorylation, reduce synaptic plasticity, and induce depressive-like behavior. Our results suggest that ketamine mediates ERK1/2 phosphorylation by downregulating A2AR expression and that p-ERK1/2 increases the production of synaptic-associated proteins, enhancing synaptic plasticity in the hippocampus and thereby ameliorating the depressive-like behavior induced by sevoflurane inhalation in rats. This research provides a framework for reducing anesthesia-induced developmental neurotoxicity and developing new antidepressants.

Cardiac hypertrophy, as one of the major predisposing factors for chronic heart failure, lacks effective interventions. Exploring the pathogenesis of cardiac hypertrophy will reveal potential therapeutic targets. S-nitrosylation is a kind of posttranslational modification that occurs at active cysteines of proteins to mediate various cellular processes. We here identified heat shock protein 90 (Hsp90) as a highly S-nitrosylated target in the hearts of rodents with hypertrophy, and the role of Hsp90 in cardiac hypertrophy remains undefined. The S-nitrosylation of Hsp90 (SNO-Hsp90) levels were elevated in angiotensin II (Ang II)- or phenylephrine (PE)-treated neonatal rat cardiomyocytes (NRCMs) in vitro as well as in cardiomyocytes isolated from mice subjected to transverse aortic constriction (TAC) in vivo. We demonstrated that the elevated SNO-Hsp90 levels were mediated by decreased S-nitrosoglutathione reductase (GSNOR) expression during cardiac hypertrophy, and delivery of GSNOR adeno-associated virus expression vectors (AAV9-GSNOR) decreased the SNO-Hsp90 levels to attenuate cardiac hypertrophy. Mass spectrometry analysis revealed that cysteine 589 (Cys589) might be the S-nitrosylation site of Hsp90. Delivery of the mutated AAV9-Hsp90-C589A inhibited SNO-Hsp90 levels and attenuated cardiac hypertrophy. We further revealed that SNO-Hsp90 led to increased interaction of glycogen synthase kinase 3β (GSK3β) and Hsp90, leading to elevated GSK3β phosphorylation and decreased eIF2Bε phosphorylation, thereby aggravating cardiac hypertrophy. Application of GSK3β inhibitor TWS119 abolished the protective effect of Hsp90-C589A mutation in Ang II-treated NRCMs. In conclusion, this study demonstrates a critical role of SNO-Hsp90 in cardiac hypertrophy, which may be of a therapeutic target for cardiac hypertrophy treatment.

Stimulation of adult cardiomyocyte proliferation is a promising strategy for treating myocardial infarction (MI). Earlier studies have shown increased CCL2 levels in plasma and cardiac tissue both in MI patients and mouse models. In present study we investigated the role of CCL2 in cardiac regeneration and the underlying mechanisms. MI was induced in adult mice by permanent ligation of the left anterior descending artery, we showed that the serum and cardiac CCL2 levels were significantly increased in MI mice. Intramyocardial injection of recombinant CCL2 (rCCL2, 1 μg) immediately after the surgery significantly promoted cardiomyocyte proliferation, improved survival rate and cardiac function, and diminished scar sizes in post-MI mice. Alongside these beneficial effects, we observed an increased angiogenesis and decreased cardiomyocyte apoptosis in post-MI mice. Conversely, treatment with a selective CCL2 synthesis inhibitor Bindarit (30 μM) suppressed both CCL2 expression and cardiomyocyte proliferation in P1 neonatal rat ventricle myocytes (NRVMs). We demonstrated in NRVMs that the CCL2 stimulated cardiomyocyte proliferation through STAT3 signaling: treatment with rCCL2 (100 ng/mL) significantly increased the phosphorylation levels of STAT3, whereas a STAT3 phosphorylation inhibitor Stattic (30 μM) suppressed rCCL2-induced cardiomyocyte proliferation. In conclusion, this study suggests that CCL2 promotes cardiac regeneration via activation of STAT3 signaling, underscoring its potential as a therapeutic agent for managing MI and associated heart failure.

It has been previously demonstrated that melatonin exerts antiarrhythmic effects under conditions of ischemia and reperfusion in vivo by maintaining a relatively high conduction velocity in the myocardium. However, mechanistical details of this effect remain unclear, specifically whether melatonin affects myocardium directly or via systemic mediating signaling. The aim of the present study was to assess the impact of melatonin on the expression of genes encoding proteins potentially responsible for maintaining myocardial conduction in cultured cardiomyocytes. Ventricular cardiomyocytes isolated from neonatal rats were incubated with melatonin (100 µM) for 24 hours. Melatonin at a concentration of 100 µM enhanced the mRNA expression level of Scn5a gene and increased the amplitude of INa sodium current in cultured neonatal rat cardiomyocytes, but did not affect the parameters of steady-state activation and inactivation of INa. Thus, the present study demonstrated the direct effect of melatonin on sodium current in cardiomyocytes.

Persistent pulmonary hypertension of the newborn (PPHN) is a common pulmonary vascular disease during the neonatal period, and it is associated with a high clinical mortality rate and a poor prognosis. At present, the treatment of PPHN is based mainly on inhaled nitric oxide (iNO), high-frequency ventilation, and pulmonary vasodilators. Sildenafil has gradually begun to be used in recent years for the treatment of PPHN and has exhibited some success; however, its detailed mechanism of action requires further elucidation. An animal model of neonatal pulmonary hypertension (neonatal rats, 48 h after birth, 10% O2, 14 days) as well as a cell model [human pulmonary artery smooth muscle cells (PASMCs), 4% O2, 60 h] were established. The effects of sildenafil on pulmonary hypertension in neonatal rats were evaluated by hematoxylin and eosin staining, immunofluorescence analysis, western blotting and PCR, and the changes in peroxisome proliferator-activated receptor γ (PPARγ), transient receptor potential canonical (TRPC)1, TRPC6 and Ki67 expression levels were detected under hypoxic conditions. The results revealed that sildenafil reversed the increases in the right ventricular mean pressure and right ventricular hypertrophy index induced by hypoxia, and attenuated pulmonary arterial remodeling as well as PASMC proliferation. The inhibitory effects of sildenafil on TRPC expression and PASMC proliferation were attenuated by GW9662 and PPARγ small interfering RNA. In conclusion, sildenafil protects against hypoxia-induced pulmonary hypertension and right ventricular hypertrophy in neonatal rats by upregulating PPARγ expression and downregulating TRPC1 and TRPC6 expression.