prostaglandin-d2 and Brain-Injuries

Prostaglandin D2 (PGD2) is the most abundant prostaglandin in the brain, but its involvement in brain damage caused by type 2 diabetes (T2D) has not been reported. In the present study, we found that increased PGD2 content is related to the inhibition of autophagy, which aggravates brain damage in T2D, and may be involved in the imbalanced expression of the corresponding PGD2 receptors DP1 and DP2. We demonstrated that DP2 inhibited autophagy and promotedT2D-induced brain damage by activating the PI3K/AKT/mTOR pathway, whereas DP1enhanced autophagy and amelioratedT2D brain damage by activating the cAMP/PKA pathway. In a T2D rat model, DP1 expression was decreased, and DP2 expression was increased; therefore, the imbalance in PGD2-DPs may be involved in T2D brain damage through the regulation of autophagy. However, there have been no reports on whether PKA can directly inhibit mTOR. The PKA catalytic subunit (PKA-C) has three subtypes (α, β and γ), and γ is not expressed in the brain. Subsequently, we suggested that PKA could directly interact with mTOR through PKA-C(α) and PKA-C(β). Our results suggest that the imbalance in PGD2-DPs is related to changes in autophagy levels in T2D brain damage, and PGD2 is involved in T2D brain damage by promoting autophagy via DP1-PKA/mTOR and inhibiting autophagy via DP2-PI3K/AKT/mTOR.

Topics: Animals; Autophagy; Blood Glucose; Body Weight; Brain Injuries; Cholesterol; Diabetes Mellitus, Type 2; Insulin; Learning; Memory; Prostaglandin D2; Rats; Rats, Sprague-Dawley; Triglycerides

In a model of closed head injury in rats, a calibrated weight drop device was allowed to fall onto the skull's convexity over the left hemisphere 1 to 2 mm lateral from the midline. Prostaglandin (PG) levels were determined in the frontal cortex region remote from the site of injury where no macroscopic damage could be seen. Differential patterns of temporal changes were evident for PGE2, PGD2, thromboxane (TX) B2, and 6-keto-PGF1 alpha in the contused hemisphere, but no changes were found in the contralateral hemisphere. The major changes in PG levels were increased levels of PGD2 and 6-keto-PGF1 alpha that persisted from 18 hours until 10 days after injury. The ratio between TXB2 and 6-keto-PGF1 alpha, which reflects the vascular tone, increased during the early postinjury period (15 minutes and 1 hour) and decreased later, up to 10 days. Thus, a sustained imbalance in favor of the vasodilator is apparent; this may suggest an improved blood supply to the region. Both PGD2 and PGI2 have protective effects in the brain. We suggest that their endogenous increase may be part of a repair mechanism at the periphery of the injured zone.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Brain Injuries; Dinoprostone; Frontal Lobe; Male; Prostaglandin D2; Prostaglandins; Prostaglandins D; Prostaglandins E; Rats; Thromboxane B2; Time Factors

Recent evidence has shown that a variety of prostaglandins and leukotrienes can be produced in brain tissue after injury in animals. It has also been speculated that increases in brain prostaglandins occur in humans following injury. Ventricular cerebrospinal fluid (CSF) samples have been obtained from children with static lesions (controls) as well as children with acute brain injury and eicosanoids measured by immunologic techniques. Metabolites of prostacyclin (6-keto-PGF1 a) and thromboxane A2 (thromboxane B2) were the major eicosanoids found in CSF, and levels of these compounds were increased 3-10 times in acutely injured patients. Prostaglandin E2 was also found in lower amounts, although in one case its level was very high. Prostaglandin D2 was also present, but in low amounts. No leukotrienes were found in CSF samples that were purified by HPLC prior to immunoassay. Elevated levels of hydroxyeicosatetraenoic acids (HETEs) were observed in those samples stored frozen, but these metabolites were most probably due to autooxidation of arachidonic acid in CSF. Arachidonic acid concentration in CSF was typically found to be in the range of 10-200 ng/ml, but was found to be 5-10 fold higher in one severely injured patient. Thus, elevated free arachidonic acid and various oxygenated metabolites were observed in CSF following brain injury.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 6-Ketoprostaglandin F1 alpha; Adolescent; Arachidonic Acid; Arachidonic Acids; Brain Injuries; Cerebral Ventricles; Child; Child, Preschool; Chromatography, High Pressure Liquid; Dinoprostone; Eicosanoic Acids; Humans; Hydroxyeicosatetraenoic Acids; Infant; Infant, Newborn; Leukotriene B4; Prostaglandin D2; Prostaglandins D; Prostaglandins E; SRS-A; Thromboxane B2