6-ketoprostaglandin-f1-alpha and Brain-Injuries

To examine the levels of thromboxane B2 (TXB2) and 6-keto prostaglandin F1alpha (6-keto PGF1alpha) production in arterial and internal jugular bulb sera in patients with traumatic brain injury (TBI). TBI is associated with arachidonate release and may be associated with an imbalance of vasoconstricting and vasodilating cyclooxygenase metabolites.. A prospective, randomized study.. The intensive care unit of a medical university hospital.. Twenty-six ventilated TBI patents (Glasgow Coma Scale score on admission, < or = 8 points) were divided randomly into two groups: a hypothermic group (n = 15), in which the patients were cooled to 32 to 33 degrees C after being giving vecuronium, midazolam, and buprenorphine; and a normothermic group (n = 11), in which the patients' body temperature was controlled at 36 to 37 degrees C by surface cooling using the same treatment as the hypothermic group. Body temperature control including normothermia was started 3 to 4 hrs after injury. The duration of hypothermia usually lasted for 3 to 4 days, after which the patients were rewarmed at a rate of approximately 1 C per day.. Blood sampling for TXB2 and 6-keto PGF1alpha was started shortly after admission in both groups. Arterial TXB2 levels on admission in both groups were elevated remarkably, but not 6-keto PGF1alpha, thereby causing an imbalance of the prostanoids after injury. In the normothermic group, TXB2 decreased transiently, but this prostanoid increased again 3 days after the injury. In the hypothermic group, such prostanoid differences disappeared shortly after therapy, and the condition was sustained for 10 days. Hypothermia attenuated differences in TXB2 levels between arterial and internal jugular bulb sera, which may reflect reduced cerebral prostanoid production. The Glasgow Outcome Scale score 6 months after the insult in the hypothermic group was significantly higher than that in the normothermic group (p = .04).. The current results from a limited number of patients suggest that moderate hypothermia may reduce prostanoid production after TBI, thereby attenuating an imbalance of thromboxane A2 and prostaglandin I2. However, it must be clarified whether the changes in the prostanoid after moderate hypothermia are a secondary effect of other mediator changes or whether they simply represent an epiphenomenon that is mechanistically unrelated to damage in TBI.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aged; Analgesics, Opioid; Arachidonic Acid; Brain Injuries; Buprenorphine; Child; Child, Preschool; Female; Glasgow Coma Scale; Glasgow Outcome Scale; Humans; Hypnotics and Sedatives; Hypothermia, Induced; Jugular Veins; Male; Midazolam; Middle Aged; Neuromuscular Nondepolarizing Agents; Prospective Studies; Prostaglandin-Endoperoxide Synthases; Thromboxane A2; Time Factors; Treatment Outcome; Vecuronium Bromide

Microvascular dysfunction, characterized by edema formation secondary to increased blood-brain barrier (BBB) permeability and decreased blood flow, contributes to poor outcome following brain trauma. Recent studies have indicated that statins may counteract edema formation following brain trauma but little is known about other circulatory effects of statins in this setting. The objective of this study was to investigate whether statin treatment improves brain microcirculation early after traumatic brain injury, and whether microvascular effects are associated with altered production of nitric oxide and prostacyclin.. After fluid percussion injury, rats were randomized to intravenous treatment with 20mg/kg of rosuvastatin or vehicle. Brain edema (wet/dry weight), BBB integrity ((51)Cr-EDTA blood to brain transfer), cerebral blood flow ((14)C-iodoantipyrine autoradiography), and number of perfused cortical capillaries (FITC-albumin fluorescence microscopy), were measured at 4 and 24h. NO and prostacyclin production was estimated from plasma concentration of the degradation products NO2- and NO3- (NOx) and 6-keto-PGF1-alpha, respectively. Sham injured animals were treated with vehicle and analyzed at 4h.. Trauma resulted in brain edema, BBB dysfunction, and reduced cortical blood flow, with no effect of statin treatment. Trauma also induced a reduction in the number of perfused capillaries, which was improved by statin treatment. Statin treatment led to increased NOx levels and reduced mean arterial blood pressure. 6-Keto-PGF1-alpha levels tended to increase after trauma, and were significantly reduced by rosuvastatin.. Rosuvastatin treatment may improve microcirculation after traumatic brain injury by preserved patency of cerebral capillaries. This effect is associated with increased NO and reduced prostacyclin production. No effect on brain edema or BBB integrity was found.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood-Brain Barrier; Brain Edema; Brain Injuries; Capillaries; Cerebrovascular Circulation; Disease Models, Animal; Edetic Acid; Epoprostenol; Fluorobenzenes; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Microcirculation; Nitric Oxide; Pyrimidines; Rats; Rats, Sprague-Dawley; Rosuvastatin Calcium; Sulfonamides; Time Factors

The implication of cyclooxygenase (COX) type 2 in post-traumatic consequences is so far controversial. In experimental models of traumatic brain injury (TBI), genetic disruption or pharmacological inhibition of COX-2 has been shown to be neuroprotective, deleterious or without effect. Therefore, the aim of our study was to investigate the effect of COX-2 inhibition against neurological deficit and brain oedema after TBI that was induced by mechanical percussion in male Swiss mice. Despite the increased level and activity of COX-2, its inhibition either with nimesulide (12 mg/kg) or meloxicam (2mg/kg) modified neither the neurological score nor the brain water content that were evaluated at 6 and 24h after injury. Interestingly, the non-selective COX inhibition with indomethacin (5mg/kg) significantly promoted neurological recovery at 6 and 24h after trauma, without improving brain oedema. In conclusion, the present study yields considerable evidence that COX-2 may not solely constitute an interesting target for the treatment of TBI consequences. Our data point to a potentially deleterious role of COX-1 in the development of neurological impairment in brain-injured mice. However, the neuroprotective mechanism of indomethacin remains to be clarified.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Behavior, Animal; Blotting, Western; Brain; Brain Edema; Brain Injuries; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Exploratory Behavior; Head Injuries, Closed; Immunoenzyme Techniques; Indomethacin; Male; Mice; Nervous System Diseases; Psychomotor Performance; Recovery of Function; Substrate Specificity

Head trauma (HT) was induced in the left hemisphere of rats by a weight drop device. Edema was maximal 24 h after HT in the injured zone, and PGE2, TXB2 and 6-keto-PGF1 alpha were elevated in both the injured and remote areas. The effect of a specific thromboxane synthetase inhibitor, OKY-046, on the outcome of HT was studied. OKY-046, 100 mg/kg, was given to rats immediately and 8 h after HT. The neurological severity score (NSS) was evaluated at 1 h after HT, and at 24 h, just prior to sacrifice. Specific gravity (SG) of both hemispheres was measured after decapitation. Prostaglandins (PGs) were extracted from the site of injury and from the frontal lobes, remote from the injury, and assayed by RIA. Basal levels of PGE2 and 6-keto-PGF1 alpha were not reduced by the drug while basal TXB2 levels were lowered. However, the increased production due to HT of all PGs, was inhibited by OKY-046, especially that of TXB2. The ratio of TXB2/6-keto-PGF1 alpha, known to affect vascular tone, was reduced by OKY-046 treatment as a result of TXA2 synthesis inhibition. Still, no effect was found on the neurological outcome (as evaluated by the NSS), or on edema formation (expressed by reduced SG). Thus, based on the present findings increased TXA2 synthesis cannot be implicated in the pathophysiology of cerebral edema or dysfunction following HT.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Animals; Brain Edema; Brain Injuries; Dinoprostone; Male; Methacrylates; Rats; Specific Gravity; Thromboxane B2; Thromboxane-A Synthase

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