Mental disorders (MD), such as anxiety, depression, and cognitive impairment, are very common during pregnancy and predispose to adverse pregnancy outcomes; however, the underlying mechanisms are still under intense investigation. Although the most common RNA modification in epigenetics, N6-methyladenosine (m6A) has been widely studied, its role in MD has not been investigated. Here, we observed that fat mass and obesity-associated protein (FTO) are downregulated in the hippocampus of pregnant rats with MD induced by fear stress and demonstrated that FTO participates in and regulates MD induced by fear stress. In addition, we identified four genes with anomalous modifications and expression (double aberrant genes) that were directly regulated by FTO, namely Angpt2, Fgf10, Rpl21, and Adcy7. Furthermore, we found that these genes might induce MD by regulating the PI3K/Akt and Rap1 signaling pathways. It appears that FTO-mediated m6A modification is a key regulatory mechanism in MD caused by fear stress during pregnancy. 

Downregulation of FTO in the hippocampus is associated with mental disorders induced by fear stress during pregnancy

Research Progress on the Mechanism of Recombinant Human Erythropoietin Intervention in Hypoxic-Ischemic Brain Injury in Premature Infants

Age-related cerebrovascular pathologies, ranging from cerebromicrovascular functional and structural alterations to large vessel atherosclerosis, promote the genesis of vascular cognitive impairment and dementia (VCID) and exacerbate Alzheimer’s disease. Recent advances in geroscience, including results from studies on heterochronic parabiosis models, reinforce the hypothesis that cell non-autonomous mechanisms play a key role in regulating cerebrovascular aging processes. Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) exert multifaceted vasoprotective effects and production of both hormones is significantly reduced in aging. This brief overview focuses on the role of age-related GH/IGF-1 deficiency in the development of cerebrovascular pathologies and VCID. It explores the mechanistic links among alterations in the somatotropic axis, specific macrovascular and microvascular pathologies (including capillary rarefaction, microhemorrhages, impaired endothelial regulation of cerebral blood flow, disruption of the blood brain barrier, decreased neurovascular coupling, and atherogenesis) and cognitive impairment. Improved understanding of cell non-autonomous mechanisms of vascular aging is crucial to identify targets for intervention to promote cerebrovascular and brain health in older adults.

/pdf/cell-non-autonomous-regulation-of-cerebrovascular-aging-fa2soqs0.pdf

Cell non-autonomous regulation of cerebrovascular aging processes by the somatotropic axis

The central nervous system is highly vulnerable to oxygen deprivation during the neonatal period, leading to long-term neurological damage. Growth hormone (GH) has shown neuroprotective and neuroregenerative effects in response to hypoxic injury. This study investigated GH effects on cell survival, inflammatory, and glial activation markers in the developing cerebellum, as well as its impact on motor coordination and anxiety-like behaviors in adulthood following neonatal hypoxia. Global hypoxia was induced in postnatal day 2 Wistar rats (8% O2, 2 h), followed by subcutaneous GH treatment (0.1 mg/kg/d) for five days. Neonatal hypoxia triggered a sustained inflammatory response in the developing cerebellum, with increased expression of TLR-4, IL-1β, TNF-α, IL-6, COX-2, iNOS, and pNF-κB, persistent gliosis, myelin disruption, and Purkinje cell loss, leading to impaired adult behavior. GH exhibited a biphasic effect—initially proinflammatory, then anti-inflammatory—ultimately downregulating proinflammatory markers and activating prosurvival pathways (pStat5, pErk1/2, pAkt, Bcl-2, TNF-R2, IGF-1). GH also reduced microglial (Iba-1) and astrocytic (GFAP) hypertrophy, restored MBP and β-III tubulin levels, enhanced Purkinje cell survival, and improved motor coordination and anxiety-like behavior in adulthood. These findings demonstrate that GH modulates the cerebellar inflammatory response and supports its therapeutic potential to counteract neuroinflammation and dysfunction following neonatal hypoxic injury. 

Growth Hormone Effects on Hypoxia-Induced Neuroinflammation in the Developing Cerebellum

Experimental in vivo data have recently shown complementary neuroprotective actions of rhEPO and growth hormone (rhGH) in a neonatal murine model of hypoxic brain injury. Here, we hypothesized that rhGH and rhEPO mediate stabilization of the blood–brain barrier (BBB) and regenerative vascular effects in hypoxic injury to the developing brain. Using an established model of neonatal hypoxia, neonatal mice (P7) were treated i.p. with rhGH (4000 µg/kg) or rhEPO (5000 IU/kg) 0/12/24 h after hypoxic exposure. After a regeneration period of 48 h or 7 d, cerebral mRNA expression of Vegf-A, its receptors and co-receptors, and selected tight junction proteins were determined using qRT-PCR and ELISA. Vessel structures were assessed by Pecam-1 and occludin (Ocln) IHC. While Vegf-A expression increased significantly with rhGH treatment (p < 0.01), expression of the Vegfr and TEK receptor tyrosine kinase (Tie-2) system remained unchanged. RhEPO increased Vegf-A (p < 0.05) and Angpt-2 (p < 0.05) expression. While hypoxia reduced the mean vessel area in the parietal cortex compared to controls (p < 0.05), rhGH and rhEPO prevented this reduction after 48 h of regeneration. Hypoxia significantly reduced the Ocln+ fraction of cortical vascular endothelial cells. Ocln signal intensity increased in the cortex in response to rhGH (p < 0.05) and in the cortex and hippocampus in response to rhEPO (p < 0.05). Our data indicate that rhGH and rhEPO have protective effects on hypoxia-induced BBB disruption and regenerative vascular effects during the post-hypoxic period in the developing brain.

https://www.mdpi.com/1422-0067/23/15/8693/pdf?version=1659691848

Further Evidence of Neuroprotective Effects of Recombinant Human Erythropoietin and Growth Hormone in Hypoxic Brain Injury in Neonatal Mice

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Further Evidence of Neuroprotective Effects of Recombinant Human Erythropoietin and Growth Hormone in Hypoxic Brain Injury in Neonatal Mice