The nongenomic neuroprotective effects of estrogen, E2-BSA, and G1 following traumatic brain injury: PI3K/Akt and histopathological study.

OBJECTIVES: Studies suggest that both genomic and nongenomic pathways are involved in mediating the salutary effects of steroids following traumatic brain injury (TBI). This study investigated the nongenomic effects of 17ß-estradiol (E2) mediated by the PI3K/p-Akt pathway after TBI. METHODS: Ovariectomized rats were apportioned to E2, E2-BSA (E2 conjugated to bovine serum albumin), G1 [G-protein-coupled estrogen receptor agonist (GPER)] or their vehicle was injected following TBI, whereas ICI (classical estrogen receptor antagonist), G15 (GPER antagonist), ICI + G15, and their vehicles were injected before the induction of TBI and injection of drugs. Diffuse TBI was induced by the Marmarou model. Evans blue (EBC, 5 h), brain water contents (BWC), histopathological changes, and brain PI3K and p-Akt protein expressions were measured 24 h after TBI. The veterinary comma scale (VCS) was assessed before and at different times after TBI. RESULTS: The results showed a reduction in BWC and EBC and increased VCS in the E2, E2-BSA, and G1 groups. Also, E2, E2-BSA, and G1 reduced brain edema, inflammation, and apoptosis. The ICI and G15 inhibited the beneficial effects of E2, E2-BSA, and G1 on these parameters. All drugs, following TBI, prevented the reduction of brain PI3K/p-Akt expression. The individual or combined use of ICI and G15 eliminated the beneficial effects of E2, E2-BSA, and G1 on PI3K/p-Akt expressions. CONCLUSIONS: These findings indicated that PI3K/p-Akt pathway plays a critical role in mediating the salutary effects of estradiol on histopathological changes and neurological outcomes following TBI, suggesting that GPER and classic ERs are involved in regulating the expression of PI3K/p-Akt.

Evaluating the neuroprotective effects of progesterone receptors on experimental traumatic brain injury: The PI3K/Akt pathway.

BACKGROUND: Studies have confirmed the salutary effects of progesterone (P4) on traumatic brain injury (TBI). This study investigated the beneficial effects of P4 via its receptors on TBI, and also whether progesterone receptors (PRs) can modulate TBI through PI3K/Akt pathway. MATERIAL AND METHODS: Marmarou method was utilized to induce diffuse TBI in ovariectomized rats. P4 (1.7 mg/kg) or the vehicle (oil) was administered 30 min after TBI induction. Moreover, RU486 (PR antagonist) and its vehicle (DMSO) were injected before TBI induction and P4 injection. Brain Evans blue content, brain water content (WC), various oxidative stress parameters, IL-1ß levels, tumor necrosis factor-α (TNF-α), histopathological alterations, and also phosphorylated Akt (p-Akt) and PI3K expressions in the brain were assessed 24 h after TBI. The veterinary comma scale (VCS) was measured before and after TBI at different times. RESULTS: The findings revealed that P4 caused an increase in VCS and a decrease in brain WC, oxidative stress, TNF-α and IL-1ß levels. RU486 inhibited the beneficial effects of P4 on these indices. Moreover, RU486 prevented the reduction of brain edema, inflammation, and apoptosis caused by P4. Moreover, P4 following TBI increased the expression of PI3K/p-Akt protein in the brain. RU486 eliminated the effects of P4 on PI3K/p-Akt expression. CONCLUSION: According to these findings, PRs are acting as critical mediators for the neuroprotective properties of P4 on oxidative stress, pro-inflammatory cytokine levels, and neurological outcomes. PRs also play an important role in regulating the PI3K/p-Akt expression and nongenomic function of P4.

Pathogenesis of COVID-19; Acute Auto-inflammatory Disease (Endotheliopathica & Leukocytoclastica COVIDicus).

BACKGROUND: The pathogenesis of the COVID19 pandemic, that has killed one million nine hundred people and infected more the 90 million until end of 2020, has been studied by many researchers. Here, we try to explain its biological behavior based on our recent autopsy information and review of literature. METHODS: In this study, patients with a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) result were considered eligible for enrollment. Histopathological examinations were done on 13 people who were hospitalized in Afzalipour hospital, Kerman, Iran. Clinical and laboratory data were reviewed. Tissue examination was done by light microscopy, immunohistochemistry and electron microscopy. RESULTS: The most frequent co-morbidity in the patients was cardiovascular disease. The common initial symptoms of COVID-19 infection were dyspnea and cough. In all cases, the number of white blood cells was higher than the normal range. Common histopathological findings were variable degrees of vasculitis as degenerative to necrotic changes of endothelium and trafficking of inflammatory cells in the vessel wall with fibrinoid necrosis. Tissue damage included interstitial acute inflammatory cells reaction with degenerative to necrotic changes of the parenchymal cells. CD34 and Factor VIII immunohistochemistry staining showed endothelial cell degeneration to necrosis at the vessel wall and infiltration by inflammatory cells. Electron microscopic features confirmed the degenerative damages in the endothelial cells. CONCLUSION: Our histopathological studies suggest that the main focus of the viral damage is the endothelial cells (endotheliopathica) in involved organs. Also, our findings suggest that degeneration of leukocytes occurs at the site of inflammation and release of cytokines (leukocytoclastica) resulting in a cytokine storm.