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Timing is a very abstract representation that shares with other magnitudes, such as numerosity, the peculiarity of being independent from any particular sensory modality. Not only we can time stimuli in different modalities but we can also compare the durations of different visual, auditory and somatosensory stimuli. Furthermore, even though time is not directly associated with space, and we are inclined to consider space and time as two different perceptual dimensions of our existence, an increasing number of studies challenge this idea by showing that timing and spatial processing have some relationship that involves sharing computation resources and that time may have a spatial representation. A more general theory, called theory of magnitude (ATOM), considers both timing and spatial computations, together with other magnitudes, as originating from a general magnitude system [Walsh VA, Trends Cogn Sci 7(11):483-8, 2003]. The neural underpinnings of time and its relationship to the processing of spatial information have started to be investigated only recently, but the field is rapidly growing. It is addressing the representation of time in several cortical and subcortical brain areas. Information processing of time and space are not strictly specialized in neural and cognitive mechanisms and we believe that studying them only separately may restrict our understanding of these processes. In this chapter, we will firstly introduce the role of the prefrontal cortex (PF) in coding relative durations. We will point out that the comparison of durations makes use of intermediate computations based on the order of the events. Secondly, we will describe the comparison mechanisms that are implemented by PF to make perceptual decisions about durations in relation to those involved in making decisions about spatial locations and distances. We will distinguish the decision processes from the goal choices, and we will examine which computational resources are shared between different magnitudes and which are domain-specific. We will summarize our results within the context of a more general PF function in promoting the generation of goals from the current context, consisting of domain- and modality-specific coding of stimuli of different modalities or magnitudes.

Several lines of evidence have postulated that reduction in the activity of lipoprotein lipase (LPL) is involved in cachexia induction in cancer patients. Recently we have demonstrated that murine melanoma B16 has the ability to reduce the LPL activity and thereby induce cachexia symptoms in mice following intraperitoneal inoculation. In order to further investigate the relationship between LPL activity and cachectic syndrome, cachexia models other than melanoma B16 are required. However, there are few animal cachexia models in which LPL activity is involved in the induction of cachectic symptoms. In this study, cachectic symptoms and plasma LPL activity were investigated in mice bearing EL-4 mouse lymphoma. In EL-4 bearing mice the body weight including tumor weight in the abdominal cavity was rather higher than that of normal mice without tumor, whereas weights of carcass wet and gastrocnemius muscle were significantly decreased in EL-4 bearing mice. Elevated blood levels of triglyceride and non-esterified fatty acid were observed in mice bearing EL-4, associated with the impaired plasma LPL activity. Overall, this study indicated that EL-4 lymphoma in mice results in a severe cachexia which is possibly related to impaired LPL activity and also provided a useful cachexia model for understanding the role of LPL in the development of cancer cachexia.

Our recent study has demonstrated that ponalrestat, an aldose reductase inhibitor, activates lipoprotein lipase activity and alleviates B16 melanoma-induced cachexia in mice. In this study, the effect of ponalrestat on murine adenocarcinoma colon26-induced cachexia was investigated in mice. Mice bearing colon26 subcutaneously lost weight and became cachectic, associated with the tumor growth. Although tumor growth was slightly stimulated when tumor bearing mice were treated with ponalrestat: nevertheless, the drug attenuated the reduction in the weight of body mass, epididymal fat, gastrocnemius muscle and carcass induced by colon26, as well as significantly prolonged the survival of the colon26 bearing mice. Ponalrestat inhibited the production of interleukin-1 (IL-1) from human monocytes stimulated by Lipopolysaccharide (LPS) in vitro, and also suppressed LPS-induced increase of IL-1 in the blood in mice. Overall, this study showed that ponalrestat suppresses IL-1 production both in vitro and in vivo, and inhibits the cachectic symptoms induced by colon26 adenocarcinoma in mice, suggesting that ponalrestat has a therapeutic potential for the treatment of cancer cachexia.

Our recent study has demonstrated that ponalrestat, an aldose reductase inhibitor, activates lipoprotein lipase (LPL) activity in the adipose tissue and alleviates the cachectic symptoms induced by B16 melanoma in mice. In this study, the effect of ponalrestat on cachexia symptoms in nude mice bearing human melanomas G361 and SEKI was investigated because it has been suggested that the suppression of LPL has an important role in cachexia induction by these two melanomas in nude mice. Mice bearing G361 subcutaneously did not gain weight and became cachectic, associated with the tumor growth. Tumor growth was not affected by ponalrestat, nevertheless treatment with ponalrestat resulted in an amelioration of the reduction in the weight of body mass, epididymal fat, gastrocnemius muscle, carcass and whole body lipid induced by the presence of G361. A severe weight loss observed in nude mice bearing SEKI was also partially attenuated by ponalrestat treatment. Overall, this study showed that ponalrestat is effective in the attenuation of the cachectic symptoms induced by human melanomas G361 and SEKI in nude mice, suggesting that ponalrestat has a potential usefulness for the treatment of cancer cachexia.

The molecular events underlying vesicular trafficking probably involve the formation and dissolution of protein complexes between integral components of the vesicle and its target membrane. SNAP-25 is associated with the plasma membrane and is a component of a core protein complex thought to be essential for neurotransmitter release. We have previously characterized a protein, hrs-2, that interacts with SNAP-25 and inhibits secretion from permeabilized PC12 cells. The cellular localization and developmental expression patterns of a number of proteins involved in the secretion machinery have been documented. To understand more about the possible cellular role of hrs-2, we have examined hrs-2 distribution, developmental expression and subcellular localization in rat tissues and cell lines. We show herein that the distribution of hrs-2 in brain and periphery parallels that of SNAP-23/25, and that recombinant hrs-2 binds to both SNAP-23 and SNAP-25. Hrs-2 mRNA and protein are found almost ubiquitously in neurons in the brain. Hrs-2 mRNA is expressed in the neural tube at E10 and thereafter mRNA and protein levels remain relatively constant in the whole brain through adulthood. In cultured PC12 cells, endogenous hrs-2 is expressed in the cytoplasm and on the limiting membranes of multivesicular bodies. Overexpression of hrs-2 in mammalian cells results in the appearance of large intracellular compartments that are labelled with hrs-2 antibodies. The wide distribution, the interaction with SNAP-23 and the localization on multivesicular body membranes suggest a general role for hrs-2 in cellular machinery.

Cancer cachexia, characterized by weight loss and progressive tissue wasting, has been postulated to be mediated by cytokines. In this study the effect of FR143430, (2-(4-fluorophenyl)-4, 5, 6, 7-tetrahydro-3-(4-pyridyl)pyrazolo[1, 5-a]pyrimidine monohydrochloride), an inhibitor of Interleukin-1 and Tumor necrosis factor-a (TNF- a), on adenocarcinoma colon26-induced cachexia was investigated in mice. Tumor growth was not affected. Nevertheless, treatment with FR143430 (0.1 to lmg) into the tumor resulted in the attenuation of the reduction in body weight, food intake, epididymal fat and carcass weight, the decrease in the circulating levels of triglyceride and glucose, and the increase in the circulating levels of total cholesterol, non esterified free fatty acid (NEFA) and total protein, which were induced by the presence of the tumor. However, oral treatment with FR143430 failed to show an inhibitory effect on cachexia induction. Overall, this study demonstrated that the cachexia induced by colon26 was alleviated by the injection of FR143430 into the tumor in sufficient quantity, without any effect on tumor growth, suggesting the potential utility of cytokine suppressive agents e for the treatment of cancer cachexia.

FK143 (4-[3-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]-1H-indol-1-yl] - butyric acid) is a new non-steroidal inhibitor of steroid 5 alpha-reductase (5 alpha-reductase). The effects of FK143 on prostate size and histopathology of mature male beagle dogs were investigated and compared with those of finasteride (a steroidal 5 alpha-reductase inhibitor), and allylestrenol and chlormadinone acetate (CMA) (androgen receptor antagonists). FK143 was orally administered to the dogs daily for 12 weeks. At doses of 10 and 32 mg/kg, FK143 significantly reduced prostate volume to about 60% of the initial value, and dogs treated with FK143 showed a dose-dependent glandular epithelial atrophy in the prostate. FK143 showed no abnormal changes in organ weights and histopathology of the adrenal, testis, pituitary and liver. The degree of prostate reduction in the dogs treated with FK143 (10 and 32 mg/kg) was almost the same as that by finasteride (1.0 mg/kg) and smaller than that by allylestrenol (10 mg/kg) or CMA (10 mg/kg). However, allylestrenol increased liver weights, and CMA increased liver and reduced adrenal weights. These results demonstrate that FK143 can decrease the volume of the dog prostate without any influence on other organs, and they suggest that FK143 is a good candidate for the treatment for benign prostatic hyperplasia.

The central effect of olopatadine (((Z)-11-[3-dimethylamino)propylidene)-6, 11-dihydrodibenz[b,e]oxepin-2-acetic acid hydrochloride, CAS 140462-76-6, KW-4679) was studied in comparison with those of ketotifen and doxepin using spontaneous EEG and EEG spectral powers in conscious rats. Both ketotifen (20 mg/kg p.o.) and doxepin (20 mg/kg p.o.) caused drowsy patterns in spontaneous EEG characterized by slow waves of high amplitude at the frontal cortex, occipital cortex and amygdala, and by disappearance of the regularity in theta waves recorded from the hippocampus. In EEG spectral powers, both drugs caused a significant increase in the power densities of the delta band recorded from the frontal cortex, occipital cortex and amygdala. On the contrary, no visible changes were elicited by the treatment with olopatadine (20 mg/kg p.o.) in both spontaneous EEG and EEG spectral powers recorded from the frontal cortex, occipital cortex, hippocampus and amygdala. These results indicate that olopatadine provides no remarkable effect on the central nervous system.

Calpain (Ca2(+)-activated neutral protease, EC 3.4.22.17) has been reported to hydrolyze the estrogen receptor (ER). However, there has been no report available regarding the role of calpain in the growth of breast cancer cells. To investigate the role of calpain in the growth of various breast cancer cell lines, we employed a synthetic peptide, calpeptin, which is a cell permeable specific inhibitor of calpain. Calpeptin inhibited the cell growth of ER positive breast cancer cells, such as MCF-7, T-47D, and ZR-75-1 in a dose dependent manner in the presence of E2. However, the growth of ER negative breast cancer cells, MDA-MB-231, was not inhibited by calpeptin. It is suggested that calpain plays an important role in the growth of ER positive breast cancer cells.

Recombinant tumor necrosis factor-alpha (rTNF-alpha) inhibited tumor growth of Meth A fibrosarcoma (Meth A) solid tumor in mice, and the antitumor effect of rTNF-alpha was significantly decreased by pretreatment with small doses or rTNF-alpha in mice. In in vitro experiments, incubation of human umbilical vein endothelial cells with rTNF-alpha enhanced procoagulant activity (PCA), which was drastically augmented after an addition of the conditioned medium of Meth A tumor cells. Furthermore, rTNF-alpha-induced PCA was decreased by pretreatment with rTNF-alpha in endothelial cells. This PCA was completely blocked after the addition of anti-human tissue factor (TF) murine monoclonal antibody. These results imply that in vivo antitumor effects of rTNF-alpha are mediated by expression of TF in endothelial cells, which is augmented by tumor released factor(s).

Tumor necrosis factor-alpha (TNF-alpha) was reported to be important in the induction of septic shock. After i.v. injection of recombinant TNF-alpha (rTNF-alpha), BALB/c mice bearing Meth A fibrosarcoma (Meth A), but not normal mice, died of shock. Tumor cells are known to release many biological components. In this study, we examined the role of the tumor in the toxicity of rTNF-alpha in mice. Meth A cells maintained i.p. in mice were cultured for 24 hr in vitro. Conditioned medium (CM) obtained from the Meth A cells was given i.v. to mice, and 2 to 7 days later, i.v. injection of rTNF-alpha induced death in the animals. rTNF-alpha treatment 4 days after Meth A CM gave the maximum effect. rTNF-alpha did not induce death in mice treated with CM from spleen cells. However, after the Meth A cells were passaged 2 or 3 times in in vitro culture, the CM did not potentiate the toxicity of rTNF-alpha in mice. rTNF-alpha induced symptoms of disseminated intravascular coagulation (DIC) on coagulation parameters in the blood, and high plasma tissue factor (TF) activity in Meth A CM-treated mice and Meth A tumor-bearing mice. These results suggest that factor(s) are released from tumor cells activated by interaction with host cells, and injection of rTNF-alpha and the factor(s) results in the induction of DIC syndrome leading to host death.

Intracerebroventricular injection of alpha-fluoromethylhistidine caused a significant decrease of the histamine content of the hypothalamus as well as of plasma adrenocorticotropic hormone and corticosterone concentrations. A high correlation was observed between the histamine content of the hypothalamus and the plasma corticosterone concentration. When the histamine content of the hypothalamus decreased, the plasma concentration of corticosterone diminished. Almost the same result was obtained when the posterior hypothalamus was lesioned electrically. The increases in plasma adrenocorticotropic hormone and corticosterone concentrations, induced by intracerebroventricular injection of histamine in sham-operated rats, were abolished after hypothalamic lesioning. When electrical stimulations were applied to the posterior hypothalamus, plasma adrenocorticotropic hormone and corticosterone concentrations increased significantly and, at the same time, evoked potentials were recorded on the adrenal nerve. An increase in plasma corticosterone concentration, induced by hypothalamic stimulation, was also observed even after hypophysectomy, suggesting that another corticosterone-secreting pathway exists apart from the hypophysis-adrenocortex system. The increase in plasma adrenocorticotropic hormone and corticosterone concentrations was inhibited not only by pyrilamine and cimetidine, but also by (R)-alpha-methyl-histamine, and H3 agonist. In addition, the effect of this latter product was inhibited by thioperamide, an H3 antagonist. These results indicate that hypothalamic histamine plays an important role in the stimulation of the corticosterone release in rats.

Changes in plasma adrenocorticotropic hormone (ACTH) and cortisol levels induced by intracerebroventricular injection of histamine (H(i)) were studied in dogs. Intracerebroventricular administration of Hi at doses of 5 and 10 micrograms/kg caused a significant increase in plasma ACTH, while more rapid and more marked increase in plasma cortisol was noticed after Hi injection at doses of 2-10 micrograms/kg. Similar results were obtained when 2-methylhistamine was injected; remarkable increases in both plasma ACTH and cortisol levels were observed at doses of 25 and 50 micrograms/kg. However, no such effect was elicited by 4-methylhistamine even at a dose of 50 micrograms/kg. The rate of plasma cortisol increase induced by either Hi or 2-methylhistamine was significantly faster than that of plasma ACTH. Simultaneous application of pyrilamine (intracerebroventricularly) with H(i) resulted in the significant inhibition of H(i)-induced hormone secretions, but in similar administration neither ACTH nor cortisol were affected by cimetidine. In hypophysectomized dogs, a significant increase in plasma cortisol level was also observed after H(i) injection at a dose of 5 micrograms/kg. Intravenous infusion of hexamethonium continued before and after H(i) injection failed to inhibit the increase in plasma ACTH and cortisol levels induced by H(i). From these findings, it can be concluded that intracerebroventricular injection of H(i) caused an increase in plasma ACTH and cortisol levels via H1-receptor, and it is suggested that to some extent, the cortisol release elicited by H(i) is certainly produced without participation of ACTH.

It is well known that the worsening of neurological findings after spinal cord injury is due to the secondary progression of pathological changes which may be caused by spinal cord blood flow disturbance. We measured spinal blood flow of 5mm rostrally and caudally distant portions from the injured point, using the laser Doppler flowmeter experimentally. Forty rats were used. Ten of these were used as a control group. And thirty animals were injured at the level of the tenth thoracic cord with a 50g epidural one minute compression method and measured continuously from 30 minutes before the injury to 6 hours after the injury. Twenty two surviving animals were evaluated. In the control group, spinal blood flow was stable. But in the injured group, spinal blood flow dropped by 30.6 + 9.8% on the rostral side and 37.3 + 17.6% on the caudal side in comparison with the resting value soon after the injury. Although the flow improved to 89.3 + 11.1 and 71.3 + 17.8% respectively 15 minutes later, it dropped again gradually and reached 42.8 + 14.1 and 66.2 + 16.4% respectively 6 hours after the injury had been inflicted. Lastly, in the animals, carbon perfusion was performed through the left ventricle. The normal figured vasculature in the preparation of the injured and measured portion was calculated with a microcomputer imaging analyzer and compared with control groups. The number of the normal vessels was significantly more abundant on the caudal side than on the rostral side (p0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

The microscopic appearance of a rat spinal cord which was acutely compressed by aneurysmal clip for one minute, was investigated 15 minutes, 30 minutes, 1 hour, 3 hours and 6 hours after the injury. Although the resulting small hemorrhagic lesion involved primarily only the central gray matter of the injured portion 15 minutes after compression injury, hemorrhage, necrosis and edema in the central gray matter enlarged progressively until 3 hours after injury. Petechial hemorrhage, necrosis and edema were observed in the surrounding area one hour after spinal compression. Then these pathological changes extended rostrally and caudally, but their extension was more significantly remarkable in the rostral side than in the caudal side 3 hours after compression. It was observed that leukocytes begin to infiltrate into the injured capillary walls and plug up the capillary lumen 30 minutes after the injury. Three hours following the injury, leukocytes (lymphocyte, macrophage) extravasated into the surrounding spinal tissue. From these histopathological observations, we reached the following conclusions. A. Secondary injuries play an important role in grave impairment of neurological function of the spinal cord following acute trauma. B. Pathological findings (hemorrhage necrosis and edema) extend more prominently to the rostral side, because the direction of spinal blood flow may be rostral in the thoracic spinal cord. C. Severe disturbance of intraspinal capillary blood flow leading to grave spinal damage may be evoked, because leukocytes infiltrate into the capillary around the injured area and plug up the their lumen about 30 minutes after the injury.

In transient cerebral ischemia, extracellular purine catabolites and pial arteriolar diameter were measured continuously. Ischemia during one hour was induced by unilateral occlusion of left middle cerebral artery in feline. Extracellular purine catabolites were sampled by in vivo brain microdialysis technique from the gray matter at ectosylvian gyrus. These catabolites were analyzed by HPLC system. Simultaneously, reactivity of pial arteriole was observed and its diameter was measured through the cranial window using intravital microscope and width analyzer. Extracellular concentrations of adenosine, inosine, hypoxanthine and xanthine were found to be 0.80 +/- 0.16 microM, 2.01 +/- 0.95 microM, 4.01 +/- 2.73 microM and 3.93 +/- 2.39 microM, respectively. During ischemia, the concentration of adenosine increased 8.7-fold and arteriolar diameter was 170% of the resting state. These findings in extracellular adenosine concentration and pial arteriolar diameter during ischemia support a role of adenosine in regulation of cerebral blood flow. After reperfusion, arteriolar diameter had returned to 120% of the resting state. But 50 min after reperfusion, pial arteriole began to dilate again coincident with the peak of xanthine concentration. These results suggest that free radicals were produced and could affect pial arterioles 50 min after reperfusion.

The focal brain ischemia with disturbance of cerebral venous drainage often lead to brain edema and hemorrhagic infarction and make mortality and morbidity worse. So we tried to make sure of this fact using a middle cerebral artery (MCA) occlusion model in adult cat. The MCA was exposed by the transorbital approach and temporally obstructed by Zen's clip. We divided the animals into two groups of eight cats. One group is only MCA occlusion group (sham group) and the other in MCA occlusion with disturbance of venous drainage (VRD group). We ligated bilateral external jugular vein (EJV) and internal jugular vein (IJV) and injected embolic sources from the left EJV to obstruct the venous system of cat brain. The pressure of superior sagittal sinus was increased up to 18.7 +/- 5.3 mmHg by this method. A cranial window was made above the ectosylvian gyrus, which has poor anastomosis. The reactivity of pial arteriole and regional cerebral blood flow (rCBF) were observed through the window. And histological brain examination was also performed. The result was that the reactivity of pial arterioles was severely disturbed in VRD group. The area of cerebral infarction and edema were also significantly expanded in VRD group. Considering from these facts, when the venous drainage was disturbed, cerebral perfusion pressure relatively decrease. Because of the decrease in cerebral perfusion pressure, cerebral infarction and edema probably expand to the area so called penumbra.

Using a middle cerebral artery occlusion model in adult cats, we investigated the ischemic time threshold for inflicting damage on cerebral vessel behavior and brain tissue. With the transorbital approach, a middle cerebral artery (MCA) was exposed and temporarily obstructed by a Zen's clip. Animals were divided into ten groups (each group: N = 8) according to the ischemic time of 10, 20, 30 minutes, 1, 2, 4, 6, 8, 12, 24 hours. Five hours after the recanalization, Evans' blue dye was injected intravenously and after further 30 minutes, the brain was fixed with transaortal perfusion for histological examinations. A cranial window was made above the ectosylvian gyrus which has poor anastomosis. The pial vessel behavior was observed through the cranial window and evaluated using an intravital microscope and a videoangiometer. Considering the correlation between functional change of vessel behavior and pathological change in the brain, the threshold time of ischemia inflicting irreversible damage was estimated. In the 30 minute ischemia group, deterioration of vessel behavior began to be observed as well as extravasation of Evans' blue dye. As the ischemic duration became longer, infarction and hemorrhage, which showed close correlation, increased. When the duration of ischemia was 6 hours, the infarcted area was significantly larger than that of the 4-hour ischemia group. Intracranial pressure (ICP) markedly increased as soon as recanalization took place. We think this phenomenon is due mainly to swelling. About three hours after recanalization, ICP further increased due to severe vasogenic edema in addition to the brain swelling.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiallergic effects of astemizole (CAS 68844-77-9) and its metabolites were studied using rats and guinea pigs. All the metabolites of astemizole tested i.e., desmethylastemizole, 6-hydroxydesmethylastemizole and norastemizole, were more active than astemizole in inhibiting the contraction of the ileum as well as the bronchoconstriction induced by histamine in guinea pigs. Desmethylastemizole was about the same as the parent compound in inhibiting the 3H-mepyramine binding in guinea pig cerebellum. In heterologous passive cutaneous anaphylaxis (PCA) and homologous PCA, the metabolites caused almost equipotent inhibition to that seen in astemizole. On the other hand, in the studies of histamine release from rat peritoneal mast cells induced by compound 48/80 or from lung fragments in actively sensitized guinea pigs, desmethylastemizole, 6-hydroxydesmethylastemizole and norastemizole were much less potent than was astemizole. No H2-antagonistic activity was observed with either astemizole or desmethylastemizole.

Temporary clipping of the major arterial trunk is a very important maneuver to control excessive unexpected bleeding during a neurosurgical operation, but repeated temporary clippings sometimes give rise to severe neurological deficits after surgery. In clinical practice, a major stroke can occur after many transient ischemic attacks without distinct angiographic occlusion. To confirm and explain these clinical experiences, the present study was performed. First, 20-min, 30-min and 1-h occlusion of the middle cerebral artery was performed in each of 5 cats, and pial arterial behavior, cerebral edema and infarction were observed. In the 20-min occlusion group, no abnormal change was found 5 hours after recirculation. In the 30-min occlusion group, cerebral edema was present in 10.5 +/- 4.2% of the hemisphere, but no infarction was observed, and pial arterial caliber remained in a 10% dilated state throughout the experimental periods. In the 1-h occlusion group, cerebral edema was present in 41.2 +/- 7.5% of the hemisphere and infarction was found in 34.5 +/- 9.5%. Pial arteries returned to a 20% dilated state but redilated by 45% at the end of experiment. As the second experiment, three 20-min occlusions at 1-h interval and two 30-min occlusions at 1-h interval were performed in each 10 cats. Pial arteries had dilated by 40% after release of the last occlusion in both groups. The extent of cerebral edema was 19.5 +/- 8.1% of hemisphere in the 20-min occlusions group and 36.6 +/- 9.7% in the 30 min occlusions group.(ABSTRACT TRUNCATED AT 250 WORDS)

Some pharmacological effects of d- and l-isomers of epinastine (WAL 801 CL, 3-amino-9,13b-dihydro-1H-dibenz [c,f]imidazo[1,5-a]azepine hydrochloride; CAS 80012-43-7) were studied in comparison with that of dl-epinastine. Although no significant difference was detected, d-epinastine is slightly more active than the l-isomer in the depressant actions of the central nervous system. However, in EEG power spectra recorded at the frontal cortex, occipital cortex, hippocampus and amygdala in conscious rats, no appreciable differences were recognized between two optical isomers and a racemic mixture. Furthermore, the extents of compound 48/80-induced lethality, antagonism on histamine-induced contraction of guinea pig ileum and histamine release from rat peritoneal mast cells were almost the same among the racemate and optical isomers of epinastine. In addition, two stereoisomers caused an almost equal degree of inhibition in antigen-induced histamine release from the lung pieces of sensitized guinea-pigs and the equivalent level of inhibition was exerted by the racemate.

In cerebral circulation, it is suspected that neurogenic or myogenic mechanism protect blood vessel and blood-brain barrier during sudden increase in arterial pressure. To discriminate metabolic mechanism from neurogenic and myogenic mechanism, complete cerebral venous occlusion model of cat was used to obtain high venous pressure. In twenty-one anesthetized cats, 0.3 ml of cyanoacrylate were injected into anterior part of SSS to occlude SSS and cortical vein. Diameter of pial vessels and ICP were measured through the cranial window. An average of ICP was 6.7 +/- 1.8 mmHg before occlusion. 5 minutes after occlusion ICP was elevated to an average of 10.4 +/- 4.8 mmHg. Finally, ICP increased over 20 mmHg in nine animals. All pial vein dilated immediately after injection of cyanoacrylate and the dilatation rate was 2-55%. Pial arteriole between 50 microns and 100 microns in diameter was observed. In early stages, 2-24% contraction of arteriole were observed in fifteen animals and 2-16% dilatation were observed in six animals. In later stages, 1-87% dilatation of arteriole were observed in ten cats. Ten of twelve ( 83%) cases with ICP under 20 mmHg showed contraction of pial arteriole. Eight of nine (89%) cases with ICP over 20 mmHg showed dilatation of pial arteriole. In addition, the elevation of ICP and the dilatation of pial arteriole were observed simultaneously. Correlation between ICP and arterial diameter is obvious. The dominant mechanism of cerebral blood flow control is metabolic, not neurogenic and myogenic. Increase of ICP, dilatation of vein and dilatation of artery with increasing ICP are consistent with the theory.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of levocabastine (R 50 547; CAS 79516-68-0) on the central nervous system were studied in comparison with those of diphenhydramine, ketotifen and azelastine. At high doses, levocabastine caused a decrease in locomotor activity, prolongation of thiopental-induced sleep, depression of acetic acid-induced writhing in mice and inhibition of active avoidance response in rats, but these adverse effects were much less potent than those seen in diphenhydramine, ketotifen and azelastine. Oxotremorine-induced tremor and salivation in mice were delayed after extremely high dosage of levocabastine; however, these were much less effective than those seen after diphenhydramine and ketotifen. Levocabastine did not affect the tonic extensor seizure induced by maximal electroshock in mice which is different from that of diphenhydramine. In EEG analysis, levocabastine at a dose of 20 mg/kg caused no significant changes in the EEG recorded from the frontal cortex, occipital cortex, hippocampus and amygdala in rats with chronic electrodes.

Retroviral infection is associated with immunosuppression, which has been shown to be due, in part, to the action of the envelope protein p15E. We studied a synthetic peptide (CKS-17) homologous to a highly conserved domain of the retroviral envelope protein p15E, which, when conjugated to BSA (CKS-17-BSA), can inhibit IL-1- and phorbol ester-mediated responses in cultured murine thymoma cells, and Ca2(+)- and phosphatidylserine-dependent protein kinase C (PKC) activity of cell homogenates. We characterized the mechanism of inhibition of PKC by the peptide. Using PKC purified from rat brain we found that CKS-17-BSA inhibited PKC-catalyzed Ca2(+)- and phosphatidylserine-dependent histone phosphorylation with an estimated ID50 of 4 microM. CKS-17-BSA did not inhibit the catalytic subunit of cAMP-dependent protein kinase. CKS-17-BSA also inhibited the Ca2(+)- and PS-independent activity of a catalytic fragment of PKC that was generated by limited trypsin treatment. However, CKS-17-BSA did not act as a competitive inhibitor of PKC with respect to ATP or phosphoacceptor substrate, despite the similarity between the CKS-17 sequence and substrates and pseudosubstrates of PKC. We conclude that this peptide homologue of a retroviral envelope protein has a novel mechanism of inhibition of PKC.