R-flurbiprofen attenuates experimental autoimmune encephalomyelitis in mice.

R-flurbiprofen is the non-cyclooxygenase inhibiting R-enantiomer of the non-steroidal anti-inflammatory drug flurbiprofen, which was assessed as a remedy for Alzheimer's disease. Because of its anti-inflammatory, endocannabinoid-modulating and antioxidative properties, combined with low toxicity, the present study assessed R-flurbiprofen in experimental autoimmune encephalomyelitis (EAE) models of multiple sclerosis in mice. Oral R-flurbiprofen prevented and attenuated primary progressive EAE in C57BL6/J mice and relapsing-remitting EAE in SJL mice, even if the treatment was initiated on or after the first flare of the disease. R-flurbiprofen reduced immune cell infiltration and microglia activation and inflammation in the spinal cord, brain and optic nerve and attenuated myelin destruction and EAE-evoked hyperalgesia. R-flurbiprofen treatment increased CD4(+)CD25(+)FoxP3(+) regulatory T cells, CTLA4(+) inhibitory T cells and interleukin-10, whereas the EAE-evoked upregulation of pro-inflammatory genes in the spinal cord was strongly reduced. The effects were associated with an increase of plasma and cortical endocannabinoids but decreased spinal prostaglandins, the latter likely due to R to S inversion. The promising results suggest potential efficacy of R-flurbiprofen in human MS, and its low toxicity may justify a clinical trial.

Intrathecal treatment with the anti-phosphorylcholine monoclonal antibody TEPC-15 decreases neuronal damage in experimental pneumococcal meningitis.

BACKGROUND: Neuronal injury in pneumococcal meningitis is a consequence of microglial activation and direct toxicity by bacterial products and systemic inflammation. METHODS: The treatment effect of the TEPC-15 antibody recognizing teichoic and lipoteichoic acids was investigated in murine microglial cells and in a rabbit model of pneumococcal meningitis. RESULTS: In vitro, the TEPC-15 antibody recognizing teichoic and lipoteichoic acids increased Streptococcus pneumoniae phagocytosis by murine microglial cells. In rabbit ceftriaxone-treated S. pneumoniae meningitis, intracisternal TEPC-15 reduced the density of apoptotic neurons in the hippocampal dentate gyrus (116 ± 70 vs. 221 ± 132/mm(2); p = 0.03). Cerebrospinal fluid inflammatory parameters (protein, lactate, leukocytes, prostaglandins) were not reduced in TEPC-15-treated rabbits. CONCLUSION: Intracisternal treatment with the TEPC-15 antibody reduced neuronal damage probably by promoting rapid phagocytosis of bacterial products.

Acute starvation alters lipopolysaccharide-induced fever in leptin-dependent and -independent mechanisms in rats.

A decrease in leptin levels with the onset of starvation triggers a myriad of physiological responses including immunosuppression and hypometabolism/hypothermia, both of which can counteract the fever response to pathogens. Here we examined the role of leptin in LPS-induced fever in rats that were fasted for 48 h prior to inflammation with or without leptin replacement (12 µg/day). The preinflammation fasting alone caused a progressive hypothermia that was almost completely reversed by leptin replacement. The LPS (100 µg/kg)-induced elevation in core body temperature (T(core)) was attenuated in the fasted animals at 2-6 h after the injection, an effect that was not reversed by leptin replacement. Increasing the LPS dose to 1,000 µg/kg caused a long-lasting fever that remained unabated for up to 36 h after the injection in the fed rats. This sustained response was strongly attenuated in the fasted rats whose T(core) started to decrease by 18 h after the injection. Leptin replacement almost completely restored the prolonged fever. The attenuation of the prolonged fever in the fasted animals was accompanied by the diminution of proinflammatory PGE(2) in the cerebrospinal fluid and mRNA of proopiomelanocortin (POMC) in the hypothalamus. Leptin replacement prevented the fasting-induced reduction of POMC but not PGE(2). Moreover, the leptin-dependent fever maintenance correlated closely with hypothalamic POMC levels (r = 0.77, P < 0.001). These results suggest that reduced leptin levels during starvation attenuate the sustained fever response by lowering hypothalamic POMC tone but not PGE(2) synthesis.

Neuroinflammatory role of prostaglandins during experimental meningitis: evidence suggestive of an in vivo relationship between nitric oxide and prostaglandins.

Nitric oxide (NO) and prostaglandins are inflammatory mediators produced during meningitis. The purpose of the present study was to pharmacologically inhibit cyclooxygenase-2 (COX-2) and inducible NO synthase (iNOS) to 1) explore the prostaglandin contribution to blood-cerebrospinal fluid barrier permeability alterations and 2) elucidate the in vivo concentration relationship between prostaglandin E2 (PGE2) and NO during experimental meningitis. Intracisternal injection of lipopolysaccharides (LPSs, 200 microg) induced neuroinflammation. Rats were dosed with nimesulide (COX-2 inhibitor), aminoguanidine (iNOS inhibitor), or vehicle. Evans blue was used to assess blood-cerebrospinal fluid barrier permeability. Meningeal NO and cerebrospinal fluid PGE2 were assayed using conventional methods. (Results are expressed as mean +/- S.E.M. of 5-9 rats/group.) Nimesulide failed to prevent blood-cerebrospinal fluid barrier disruption [cerebrospinal fluid Evans blue (micrograms per milliliter): control, 0.22 +/- 0.22*; LPS, 11.58 +/- 0.66; LPS + nimesulide, 10.58 +/- 0.86; *p < 0.05; ANOVA]. Although nimesulide decreased PGE2 (picograms per microliter; p < 0.01) in LPS + nimesulide rats (13.9 +/- 1.96) versus LPS + vehicle (73.8 +/- 12.4), meningeal NO production (picomoles/30 min/10(6) cells; p < 0.01) increased unexpectedly in LPS + nimesulide rats (439 +/- 47) versus LPS + vehicle rats (211 +/- 31). In contrast, aminoguanidine inhibited meningeal NO (picomoles/30 min/10(6) cells; p < 0.005) in LPS + aminoguanidine (111 +/- 20) versus LPS (337 +/- 48) but had no effects (p > 0.05) on PGE2. The in vivo relationship between PGE2 and NO was mathematically described by a biphasic, bell-shaped curve (r2 = 0.42; n = 27 rats; p < 0.0001). Based on these results, inhibition of prostaglandin synthesis not only fails to prevent blood-cerebrospinal fluid barrier disruption during neuroinflammation and but also promotes increased meningeal NO production. The in vivo concentration relationship between PGE2 and NO is biphasic, suggesting that inhibition of COX-2 alone may promote NO toxicity through enhanced NO synthesis.

Pharmacology of celecoxib in rat brain after kainate administration.

Prostaglandin E(2) (PGE(2)) is the major prostaglandin produced both centrally and in the periphery in models of acute and chronic inflammation, and its formation in both locations is blocked by cyclooxygenase-2 (COX-2) inhibitors such as celecoxib. In animal models of inflammation, PGE(2) inhibition in the brain may occur secondarily to a peripheral action by inhibiting local PG formation that elicits increased firing of pain fibers and consequent activation of PG synthesis in the central nervous system (CNS). Celecoxib was studied in the kainate-induced seizure model in the rat, a model of direct central prostaglandin induction, to determine whether it can act directly in the CNS. In the kainate-treated rat brain there was increased PGE(2), PGF(2alpha), and PGD(2) production, with COX activity and PGE(2) formation increased about 7-fold over normal. We quantitated mRNA levels for enzymes involved in the prostaglandin biosynthetic pathways and found that both COX-2 and PGE synthase (PGEs) mRNA levels were increased in the brain; no changes were found for expression of COX-1 or PGD synthase mRNA. By Western blot analysis, COX-2 and PGEs were induced in total brain, hippocampus, and cortex, but not in the spinal cord. Immunohistological studies showed that COX-2 protein expression was enhanced in neurons. Dexamethasone treatment reduced the expression of both COX-2 and PGEs in kainate-treated animals. Celecoxib reduced the elevated PGE(2) levels in brain of kainate-treated rats and inhibited induced COX activity, demonstrating the ability of this compound to act on COX-2 in CNS. Doses of celecoxib that inhibited brain COX-2 were lower than those needed for anti-inflammatory activity in adjuvant arthritis, demonstrating a potent direct central action of the compound.

Simultaneous assay of prostaglandins and thromboxane in the cerebrospinal fluid by gas chromatography-mass spectrometry-selected ion monitoring.

A method of simultaneous analysis of prostaglandins (PGs) and thromboxane (TX) B2 in cerebrospinal fluid (CSF) with GC-MS-SIM was established. Deuterated PGs and TXB2 were used as internal standards: tetra-deuterated PGE2 (d4-PGE2) for PGE2, PGE1 and PGD2; d5-PGF2alpha for PGF2alpha and 9alpha,11beta-PGF2 and 8-epi PGF2alpha; d4-TXB2 for TXB2; and d4-6-keto PGF1alpha for 6-keto PGF1alpha. The PGs and TXB2 were derivatized to the methyl ester of the methoxim dimethyisopropylsilyl (DMiPSi) ether form or the methyl ester of the DMiPSi ether form with simultaneous preparation. Samples were extracted with octadecyl silica gel and purified in two steps with silisic acid gel chromatography between derivatization steps. The calibration curve of each PG and TXB2 was linear from 10 pg to 10 ng with the isotope dilution method. The levels of the seven types of PG and of TXB2 were assayed simultaneously in the cerebrospinal fluid (CSF) from patients with aseptic meningitis. The CSF pattern of the PG and TXB2 concentrations in mumps meningitis differed from those in other types of aseptic meningitis and in disease controls.

Cerebrospinal fluid prostaglandins and corticotropin releasing factor in schizophrenics and controls: relationship to sleep architecture.

Sleep abnormalities have been consistently observed in patients with schizophrenia. Elevated levels of corticotropin releasing factor (CRF) and prostaglandins (PGs) in the cerebrospinal fluid (CSF) of patients with schizophrenia have been reported, and these neurochemical substances, known to modulate sleep in experimental animals, may play a role in these sleep abnormalities. In this study, we measured PGD2, PGE2, PGF2alpha and CRF levels in the CSF of 14 unmedicated schizophrenic patients and 14 age- and sex-matched control subjects. Polysomnographic recordings were also carried out for each subject. As expected, the sleep of the schizophrenic subjects significantly differed from that of the controls; schizophrenic subjects had a longer sleep onset latency, slept less, spent fewer minutes in stage 2 sleep and had a lower sleep efficiency. We could not, however, detect any differences in CSF CRF and PG levels between normal and schizophrenic subjects, nor could we find any correlation between CSF variables and sleep parameters in the schizophrenic subjects and the non-psychiatric controls. These results do not favor the hypothesis of a role for CRF or PGs in the pathophysiology of sleep disturbances in schizophrenia.

Altered release of prostaglandins by opioids contributes to impaired cerebral hemodynamics following brain injury.

OBJECTIVES: After fluid percussion brain injury (FPI) in the newborn pig, pial arteries constrict and responses to dilator stimuli, including opioids, are blunted. This study was designed to determine if altered release of prostaglandins contributes to blunted opioid dilation of cerebral arteries in newborn piglets following brain injury. DESIGN: Prospective, in vivo, cerebral hemodynamic animal study. SETTING: University research laboratory. SUBJECTS: Newborn (1- to 5-days old) piglets of either gender. INTERVENTIONS: In anesthetized, newborn, 1- to 5-day-old pigs, a closed cranial window was used to measure pial artery diameter and to collect cortical periarachnoid cerebrospinal fluid (CSF) for determination of 6-keto-PGF1alpha, the stable metabolite of prostaglandin I2 (PGI2) and thromboxane B2 (TXB2), the stable metabolite of TXA2, via radioimmunoassay. FPI of moderate severity (1.9 to 2.3 atmospheres) was produced by using a pendulum to strike a piston on a saline-filled cylinder that was fluid coupled to the brain via a hollow screw inserted through the cranium. MEASUREMENTS AND MAIN RESULTS: Methionine enkephalin (Met) vasodilation was blunted after FPI but was partially restored with indomethacin pretreatment (5 mg/kg i.v.) (8 +/- 1 [SEM] %, 13 +/- 1%, and 20 +/- 1% vs. 1 +/- 1%, 3 +/- 1%, and 5 +/- 1% vs. 7 +/- 1%, 10 +/- 1%, and 15 +/- 1%, respectively, for 10(-10), 10(-8), and 10(-6) M Met during control conditions, after FPI, and after FPI pretreated with indomethacin, n = 6). Similarly, restoration of Met dilation after FPI was observed with SQ 29,548, a TXA2 antagonist. Met-induced 6-keto-PGF1alpha release was blunted following FPI (889 +/- 20, 1130 +/- 33, and 1886 +/- 59 vs. 2630 +/- 36, 2775 +/- 30, and 2825 +/- 36 pg/mL for control, 10(-10), and 10(-6) M Met before and after FPI, respectively, n = 6). In contrast, Met-induced TXB2 release was enhanced after FPI (340 +/- 20, 423 +/- 25, and 473 +/- 30 pg/mL vs. 518 +/- 30, 726 +/- 90, and 901 +/- 35 pg/mL for control, 10(-10), and 10(-6) M Met before and after FPI, respectively, n = 6). Leucine enkephalin- and dynorphin-induced dilation and associated prostaglandin release were similarly altered following FPI. Beta endorphin-induced constriction was enhanced following FPI, and these potentiated responses were blunted after indomethacin or SQ 29,548 pretreatment. CONCLUSIONS: These data show that FPI increases CSF 6-keto-PGF1alpha and TXB2 concentrations. These data suggest that altered release of prostaglandins by opioids contribute to impaired cerebral hemodynamics following FPI in piglets.

Effects of continuous infusion fentanyl citrate on cerebrovascular and systemic prostanoids in postsurgical newborn piglets.

BACKGROUND: Newborns admitted to the intensive care unit undergo multiple painful procedures. Fentanyl citrate (FC) is one of the most commonly used drugs for pain relief in the newborn. Although it has been reported that one of the biological effects of fentanyl is hemodynamic stability, the response of systemic and/or cerebrovascular prostanoids to FC infusions have not been studied. METHODS: To examine the effects of continuous intravenous (IV) infusion of FC on systemic and cerebrovascular prostanoid concentrations, two groups of spontaneously breathing newborn piglets (1-3 days old) were studied. The study group (n = 6) and the control group (n = 8) were respectively given a loading dose of 30 micrograms/kg IV over 15 minutes, immediately followed by a continuous IV infusion of 10 micrograms/kg/hr for 6 hours, or a placebo (PB) solution of 5% dextrose in a similar fashion. Cerebrospinal fluid (0.5 mL) from cisterna magna puncture and blood samples (1.0 mL) from the sagittal sinus vein and carotid artery were collected serially before and after FC or PB infusion for drug and PG determinations. FC was measured by high pressure liquid chromatography (HPLC), and the prostanoids were measured using enzyme immunoassay (EIA) kits. RESULTS: FC infusion induced marked elevations in 6-ketoPGF1 alpha (300%, p < 0.001) and TXB2 (150%, p < 0.001) at 30 minutes, and remained elevated up to 2 hours of infusion. In addition, systemic 6-ketoPGF1 alpha increased by 180% (p < 0.001) and PGE2 concentrations fell dramatically at 30 minutes (87%, p < 0.001) and did not return to normal levels during the infusion time (83% to 81%, p < 0.001 to p < 0.01). CSF 6-ketoPGF1 alpha and TXB2 levels increased by 152% and 80%, respectively (p < 0.001), but PGE2 decreased by 76% (p < 0.001), at 6 hours of infusion. An inverse relationship existed between FC, and sagittal sinus PGE2 levels (r = 0.46, p < 0.03) and systemic PGE2 levels (r = 0.602, p < 0.02). CONCLUSION: The data suggest FC is rapidly transported across the blood brain barrier and the effects on cerebrovascular prostanoids, particularly PGE2 is rapid and prolonged. PGE2 appears to be the primary responsive prostanoid. The magnitude of the response, as evidenced by the early and sharp reductions in systemic and cerebrovascular concentrations, suggest vasoconstriction, with possible adverse effects on organ blood flow and metabolic activity. However, further studies are required to evaluate the effects on organ blood flow and metabolism.

Multiple mechanisms mediate antipyretic action of glucocorticoids.

Glucocorticoids inhibit various components of the acute phase response, particularly the increase in body temperature (fever) induced by a variety of stimuli. In the present study these observations have been extended, and we have determined the effect of glucocorticoid treatment or surgical adrenalectomy on the cytokine and prostaglandin (PG) concentrations in plasma and cerebrospinal fluid (CSF) during the febrile response to endotoxin. Dexamethasone treatment, either before or after endotoxin injection, markedly inhibited fever and the increased plasma interleukin (IL)-6 and CSF IL-6, PGE2, and PGF2 alpha concentrations. Adrenalectomized (ADX) rats showed higher fevers and plasma and CSF IL-6, PGE2, and PGF2 alpha, concentrations compared with sham-operated animals and exhibited a lower plasma-to-CSF IL-6 ratio than sham-operated animals. Dexamethasone pretreatment also inhibited fever induced by centrally injected TNF-alpha, IL-1 beta, or IL-6. Pyrogenic response to IL-8 was not modified by indomethacin but was markedly inhibited by prior treatment with dexamethasone. These results support the hypothesis that endogenous glucocorticoids function as part of an inhibitory feedback system involved in the modulation of fever and that multiple mechanisms may be involved in their antipyretic effect.

Actinomycin D blocks interleukin-1 alpha-induced pial arteriolar dilation and increased prostanoid production in newborn pigs.

Effects of protein synthesis and cyclooxygenase inhibitors on interleukin-1 alpha (IL-1 alpha)- and histamine-induced pial arteriolar dilation and cerebrospinal fluid (CSF) prostanoid increases were examined in anesthetized piglets using closed cranial windows. Topical IL-1 alpha (10.8 micrograms) increased pial arteriolar diameter from 15 to 30 min after its infusion, and enhanced CSF prostanoids. Topical protein synthesis inhibitor, actinomycin D, at a concentration of 10(-8) M attenuated and 10(-6) M completely blocked both IL-1 alpha-induced vasodilation and CSF prostanoid increase. Inhibition of prostaglandin H synthases with indomethacin blocked both vasodilation and CSF prostanoid increase by IL-1 alpha. Topical histamine (10(-6) M) also increased pial arteriolar diameter and CSF prostanoids but without the delay seen between IL-1 alpha infusion and responses. These histamine effects were not modified by coinfusion of actinomycin D but blocked by indomethacin. These results suggest that, although IL-1 alpha and histamine do share the same mechanism insofar as activation of prostaglandin synthesis is concerned, an additional step appears to be involved for IL-1 alpha, likely involving de novo protein synthesis.

Subarachnoid blood causes pial arteriolar constriction in newborn pigs.

BACKGROUND AND PURPOSE: The present study was designed to determine in newborn animals the delayed effect of subarachnoid blood on pial arteriolar diameter and eicosanoid concentrations in cortical periarachnoid fluid. METHODS: Forty-eight to 96 hours after subarachnoid blood installation, closed cranial windows were implanted over the cerebral area exposed to blood in anesthetized, artificially ventilated newborn piglets. All pial arterioles greater than 60 microns in diameter were measured, and cortical periarachnoid fluid was collected for the determination of eicosanoids. RESULTS: Subarachnoid blood resulted in a 20% to 30% decrease in the average diameter of pial arterioles exposed to blood for 48 to 96 hours, a decreased number of large pial arterioles (greater than 200 microns), and an increased number of small arterioles (60 to 100 microns). No changes in dilator prostanoids (prostacyclin [as 6-keto-prostaglandin F1 alpha] and prostaglandin E2) were detected. Concentrations of vasoconstrictor prostanoids in cortical cerebrospinal fluid increased. Thromboxane B2 increased to 430 +/- 70 pg/mL, and prostaglandin F2 alpha increased to 1370 +/- 180 pg/mL compared with 250 +/- 20 and 860 +/- 70 pg/mL, respectively, in the control group. The concentration of peptidoleukotrienes increased to 400 to 600 pg/mL 72 to 96 hours after blood installation, while the level in the control group was less than 80 pg/mL. CONCLUSIONS: The altered balance between vasodilator and vasoconstrictor eicosanoids could contribute to cerebral vasoconstriction after subarachnoid blood installation in newborn pigs.

Pial arteriolar constriction following cortical spreading depression is mediated by prostanoids.

The mechanism of pial arteriolar constriction during post-cortical spreading depression (CSD) was examined in anesthetized adult rabbits. Using a closed cranial window and intravital microscopy, the diameter of a pial arteriole was determined. A single CSD was induced by KCl micro-injection and its propagation was monitored by recording slow potential changes accompanying CSD. Prostanoid levels in cortical cerebrospinal fluid (CSF) were determined by radioimmunoassay. Pial arteriolar diameter increased significantly from 76 +/- 6 to a maximum of 119 +/- 5 microns (57%, n = 8) for 1.6 +/- 0.1 min when CSD (velocity, 2.8 +/- 0.1 mm/min) reached the cortex just beneath the vessel irrespective of its location. Shortly after CSD expiration from the cortex, pial arteriolar diameter decreased from the pre-CSD level to a minimum of 67 +/- 5 microns (12%, n = 8) for 19.5 +/- 2.1 min. CSD was elicited again in the same animal while the cortical surface under the window was continuously superfused with artificial CSF at a flow rate of 3.2-4.5 ml/min. Pial arteriolar dilation (from 75 +/- 6 to 115 +/- 3 microns, 53 +/- 9%, for 1.6 +/- 0.1 min, n = 8) was observed again during CSD (velocity, 2.7 +/- 0.2 mm/min), however, no constriction of the vessel was seen after CSD expiration. Indomethacin pretreatment (n = 11) to inhibit prostanoid production enhanced the magnitude of CSD-induced vasodilation from the pretreatment levels of 59 +/- 9% (from 82 +/- 5 to 130 +/- 8 microns for 1.7 min) to the post-treatment levels of 82 +/- 13% (from 78 +/- 5 to 142 +/- 12 microns for 1.8 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of phorbol esters on pial arteriolar diameter and brain production of prostanoids in piglets.

We determined the effects of phorbol 12,13-dibutyrate (PDB), which activates protein kinase C, on pial arteriolar diameter and cerebrospinal fluid (CSF) prostanoid levels in newborn pigs. A closed cranial window was implanted, and the diameter of one pial arteriole was determined by intravital microscopy. In addition, CSF was sampled from under the window, and prostanoid levels (prostaglandin [PG] E2, 6-keto-PGF1 alpha, PGF2 alpha, and thromboxane B2) were determined by radioimmunoassay. Diameter and CSF prostanoid levels were determined during application of artificial CSF containing no drugs and during application of 10(-8), 10(-7), and 10(-6) M PDB. We also determined effects of 4 alpha-phorbol 12,13-didecanoate (4 alpha-PDD), a phorbol ester that does not activate protein kinase C, and dimethyl sulfoxide, the vehicle for the phorbol esters, on pial arteriolar diameter and CSF prostanoid levels. Initial diameters were 100-200 microns. At 10(-8)-10(-6) M, PDB progressively constricted pial arterioles and increased CSF levels of prostanoids; the other phorbol ester and dimethyl sulfoxide had no such effects. Baseline arteriolar diameter was 147 +/- 17 microns (mean +/- SEM), and diameter was 140 +/- 17 microns at 10(-8) M PDB, 120 +/- 18 microns at 10(-7) M PDB (p less than 0.05), and 108 +/- 14 microns at 10(-6) M PDB (p less than 0.05) (n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Prostanoids attenuate pial arteriolar dilation induced by cortical spreading depression in rabbits.

The role of prostanoids in mediating cerebrovascular responses to cortical spreading depression (CSD) was examined in anesthetized rabbits. CSD was elicited by KCl microinjection, and its propagation was monitored electrophysiologically. Pial arterial diameter was determined using a closed cranial window and intravital microscopy, and regional cerebral blood flow (rCBF) was determined using laser flowmetry. Levels of peri-arachnoid cerebrospinal fluid prostanoids were determined by radioimmunoassay. CSF increased pial arteriolar diameter 62% and rCBF 354% over the baseline levels. Locations of propagating CSD, dilating pial arteriole, and increased rCBF were always closely associated spatiotemporally. Cerebrospinal fluid prostanoid levels increased during single CSD-induced arteriolar dilation, and they were further augmented during multiple CSDs. Indomethacin enhanced both CSD-induced vasodilation (88%) and rCBF increase (580%), but it decreased the cerebrospinal fluid levels of prostanoids below the baseline levels and prevented their increase during CSD-induced vasodilation. These results indicate that prostanoids are synthesized from neurons or glial cells and/or the brain vessels and, as the net result, counteract pial arteriolar dilation and rCBF increase during CSD. In addition, they support the hypothesis that the vasodilation is caused primarily by neurogenic factors associated with CSD.

CSF and endocrine studies of premenstrual syndrome.

Eight women with prospectively documented premenstrual syndrome (PMS) underwent multiple samplings for estradiol, progesterone, prolactin, cortisol, and plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) during an asymptomatic midcycle (late follicular) and a symptomatic premenstrual (late luteal) phase of the menstrual cycle. Cerebrospinal fluid (CSF) was collected for analysis of MHPG, norepinephrine (NE), 5-hydroxyindoleacetic acid (5-HIAA), dihydroxyphenylacetic acid (DOPAC), gamma-aminobutyric acid (GABA), homovanillic acid (HVA), tyrosine, tryptophan, beta-endorphin, prostaglandins, adrenocorticotropic hormone (ACTH), and arginine vasopressin (AVP). In subsequent months, a dexamethasone suppression test (DST) and a thyrotropin-releasing hormone (TRH) stimulation test were performed during midcycle and premenstrual phases. Significant results included increased CSF concentrations of MHPG in the premenstrual, as compared with the midcycle, phase of the cycle, and increased plasma cortisol concentrations during the midcycle phase. The DST showed a 62% overall rate of nonsuppression, irrespective of menstrual cycle phase. Though there were no abnormalities of thyrotropin-stimulating hormone (TSH) after TRH stimulation, the mean delta maximum prolactin values after TRH stimulation were higher than reported normal values both at midcycle and premenstrually. These pilot data suggest hormonal axes that might be worthy of further systematic investigation in future studies of PMS.

Cerebrospinal fluid eicosanoid levels: endogenous PGD2 and LTC4 synthesis by antigen-presenting cells that migrate to the central nervous system.

We analyzed CSF from patients with multiple sclerosis, patients with other neurologic diseases, and healthy controls for the presence of prostaglandin (PG) E2, F2 alpha, D2, I, A, and leukotriene (LT) C4. Control CSF had little measurable PGs or LTs. CSF eicosanoids from patients with progressive MS were increased. We found PGD2 only in MS CSF. CSF monocytes from patients in active disease produced significantly increased PGD, PGE, and LTC4 than paired peripheral blood monocytes and monocytes from healthy controls. We saw no significant difference in LTC4 production between MS and control peripheral blood monocytes.

Prostanoids modulate opioid cerebrovascular responses in newborn pigs.

The influences of opioids on pial arteriolar diameter and cortical periarachnoid cerebrospinal fluid prostanoid concentration were investigated in piglets with closed cranial windows. Methionine enkephalin (10(-12)-10(-6) M) increased pial arteriolar diameter (139 +/- 4, 149 +/- 3, 178 +/- 3 microns, for control, 10(-12), and 10(-6) M, respectively). Leucine enkephalin produced similar pial arteriolar dilation. In contrast, dynorphin elicited dilation during normotension and constriction during hypotension. beta-Endorphin (10(-12)-10(-6) M) decreased pial arteriolar diameter (137 +/- 6, 128 +/- 6, 92 +/- 7 microns, for control, 10(-12) and 10(-6) M, respectively). All four opioids increased cerebrospinal fluid 6-keto-prostaglandin (PG)F1 alpha, PGE2, PGF2 alpha and thromboxane B2. Indomethacin (5 mg/kg i.v.) blocked methionine and leucine enkephalin and dynorphin-induced pial arteriolar dilation, but potentiated beta-endorphin-induced constriction and the constriction caused by dynorphin in hypotensive piglets. These data indicate that prostanoids modulate opioid effects on the cerebral vasculature.