Search PubMed⌕ Search

Biomedical subjects

P L Wood

Publications and source records attributed to P L Wood.

At least 19 recordsLinked to original sources
PubMed1997

Anxiolytic and anticonvulsant activity of a synthetic neuroactive steroid Co 3-0593.

Endogeneously occurring neuroactive steroids, metabolites of progesterone and deoxycorticosterone, have been shown previously to interact with the GABAA receptor with great specificity in vitro and to have anticonvulsant, anxiolytic and sedative activity in vivo. However, these endogenously occurring steroids are not useful as therapeutic agents due to their potential metabolism to hormonally active steroids and their poor oral bioavailability. In an attempt to develop therapeutic agents which would maintain the pharmacological profiles of endogeneous neuroactive steroids but with increased oral bioavailability and reduced metabolic liability, we explored simple substitutions at the 3 beta-position of the endogenous neuroactive steroid, 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha, 5 alpha-P). This report describes part of the in vitro and in vivo pharmacological profile of a 3 beta-substituted analog, 3 beta-ethenyl-3 alpha-hydroxy-5 alpha-pregnan-20-one (Co 3-0593). The compound exhibited anticonvulsant activity against pentylenetrazol-induced seizures in mice and rats (ED50 = 5.6 and 11.5 mg/kg, i.p., respectively). Co 3-0593 showed robust anxiolytic effects, comparable to benzodiazepines in the Geller-Seifter test after both SC and oral administration. Furthermore, the anxiolytic activity was maintained after chronic administration suggesting an absence of tolerance. The compound did not affect the acquisition of a learned response at both anticonvulsant and anxiolytic doses. However, at higher doses the compound showed rotorod deficit which was further enhanced by ethanol. In summary, 3 beta-ethenyl-substituted 3 alpha, 5 alpha-P appeared to maintain the pharmacological activities of the endogenous neuroactive steroid with apparent oral activity.

Animals↗
PubMed1997

Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; 3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one), a selective, high-affinity, steroid modulator of the gamma-aminobutyric acid(A) receptor.

Ganaxolone (CCD 1042) is a 3beta-methyl-substituted analog of the endogenous neuroactive steroid 3alpha-hydroxy-5alpha-pregnan-20-one. Ganaxolone inhibited binding of the gamma-aminobutyric acid (GABA)A receptor-chloride channel ligand t-[35S]butylbicyclophosphorothionate (IC50 of 80 nM) and enhanced binding of the benzodiazepine site ligand [3H]flunitrazepam (EC50 of 125 nM) and the GABA site ligand [3H]muscimol (EC50 of 86 nM), consistent with activity as a positive allosteric modulator of the GABA(A) receptor. Electrophysiological recordings showed that, whereas nanomolar concentrations of ganaxolone potentiated GABA-evoked chloride currents in Xenopus oocytes expressing the human GABA(A) receptor subunits alpha1beta1gamma2L, alpha2beta1gamma2L or alpha3beta1gamma2L, direct activation of chloride flux occurred to a limited extent only at micromolar concentrations. Ganaxolone was effective in nontoxic doses against clonic convulsions induced by s.c. pentylenetetrazol administration in mice and rats (ED50 values of 4.3 and 7.8 mg/kg i.p., respectively). Ganaxolone also exhibited potent anticonvulsant activity against seizures induced by s.c. bicuculline (ED50 of 4.6 mg/kg i.p.), i.p. TBPS (ED50 of 11.7 mg/kg i.p.) and i.p. aminophylline (ED50 of 11.5 mg/kg i.p.) in mice. Although ganaxolone effectively blocked tonic seizures induced by maximal electroshock in mice (ED50 of 29.7 mg/kg i.p.), it did so only at doses that produced ataxia on the Rotorod (TD50 of 33.4 mg/kg i.p.). Conversely, ganaxolone was a potent anticonvulsant against fully kindled stage 5 seizures induced by corneal kindling in rats (ED50 of 4.5 mg/kg i.p.), producing these effects at doses well below those that resulted in ataxia (TD50 of 14.2 mg/kg i.p.). The seizure threshold, as determined by an increase in the dose of i.v. infused pentylenetetrazol required to induce clonus, was also significantly elevated by nontoxic doses of ganaxolone in mice. In summary, these data indicate that ganaxolone is a high-affinity, stereoselective, positive allosteric modulator of the GABA(A) receptor complex that exhibits potent anticonvulsant activity across a range of animal procedures. The profile of anticonvulsant activity obtained for ganaxolone supports clinical evaluation of this drug as an antiepileptic therapy with potential utility in the treatment of generalized absence seizures as well as simple and complex partial seizures.

Animals↗
PubMed1997

CCD-3693: an orally bioavailable analog of the endogenous neuroactive steroid, pregnanolone, demonstrates potent sedative hypnotic actions in the rat.

An endogenous neuroactive steroid, pregnanolone, and an orally available synthetic analog, CCD-3693, were administered to rats at the middle of their circadian activity phase (6 hr after lights off). Electroencephalogram-defined sleep-wake states, locomotor activity and body temperature were concurrently measured 30 hr before and after treatment. Identical procedures were used to test triazolam and zolpidem. Triazolam (0.1-1.6 mg/kg), zolpidem (2.5-10 mg/kg) and the neuroactive steroids (10-30 mg/kg) produced dose-dependent increases in non-rapid eye movement (NREM) sleep. At this dose and time of day (in which the rats were predominantly awake during the 6 hr before treatment) the neuroactive steroids appeared more intrinsically efficacious in promoting NREM sleep than the benzodiazepine ligands. The neurosteroids did not, however, significantly interfere with rapid eye movement sleep and were more selective in reducing (EEG) wakefulness, with relatively less locomotor activity impairment during waking than triazolam and zolpidem. In addition, the benzodiazepine receptor ligands showed distinct "rebound" wakefulness after the NREM sleep-promoting effect subsided, although the neuroactive steroids did not. In addition, in vitro binding studies and in vivo pharmacological data confirmed that CCD-3693 was orally active in standard tests of anxiety, anticonvulsant, loss-of-righting and passive avoidance.

Administration, Oral↗
PubMed1996

The metabotropic glutamate receptor antagonist L-2-amino-3-phosphonopropionic acid inhibits phosphoserine phosphatase.

Phosphoserine phosphatase catalyzes the final step in the major pathway of L-serine biosynthesis in brain. Using D-phosphoserine as substrate, the metabotropic glutamate receptor antagonist L-2-amino-3-phosphonopropionic acid (L-AP3) inhibits phosphoserine phosphatase partially purified from rat brain with a Ki of 151 microM. In contrast to AP3 enantioselectivity at metabotropic receptors, D-AP3 (Ki 48 microM) is more potent as an inhibitor of phosphoserine phosphatase than L-AP3, whereas DL-AP3 has intermediate potency. D-, L-, and DL-AP3 are 6- to 8-fold more potent inhibitors using D-phosphoserine rather than L-phosphoserine as substrate, suggesting that AP3 may have selectivity for isoforms of phosphoserine phosphatase which preferentially cleave D-phosphoserine. D-AP3 decreases the apparent affinity of D- and L-phosphoserine with little or no change in maximal velocity indicating that it is a competitive inhibitor of the enzyme. Whereas L-AP3 has similar potency at metabotropic glutamate receptors and phosphoserine phosphatase, D-AP3 is selective for phosphoserine phosphatase and is the most potent and only known competitive inhibitor of this enzyme.

Alanine↗
PubMed1996

Steroid inhibition of [3H]SR 95531 binding to the GABAA recognition site.

The interaction of three types of steroids with the GABAA recognition site labeled by the antagonist ligand [3H]SR 95531 was evaluated in rat brain cortical membranes. The first type is the GABA site antagonist RU 5135, which potently (IC50 7 nM) but also incompletely (Imax 82%) displaced [3H]SR 95531. RU 5135 probably binds only to high affinity [3H]SR 9553] sites recognized by GABA and unlabelled SR 95531. The second type are the neuroactive steroids which act as positive allosteric modulators, including 3 alpha-hydroxy-5 beta-pregnan-20-one (3 alpha, 5 beta-P) and 5 beta-tetrahydrodeoxycorticosterone (5 beta-THDOC), which inhibited [3H]SR 95531 binding with limited efficacy (IC50 460 nM and 1.4 microM, Imax 41 and 31%, respectively). In contrast, 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha, 5 alpha-P) was inactive. The third type are the neurosteroids acting as negative allosteric modulators, such as pregnenolone sulfate, which inhibited [3H]SR 95531 binding with limited efficacy (IC50 10 microM, Imax 23%). In the presence of a saturating concentration of pregnenolone sulfate, 3 alpha, 5 beta-P further inhibited [3H]SR 95531 binding suggesting that these two steroids act through different sites or, possibly, at different populations of GABAA receptors. The allosteric modulation was selective for steroids since benzodiazepines and barbiturates were inactive up to 100 microM. Taken together, these data suggest that 3 alpha, 5 beta-P and 5 beta-THDOC modulate [3H]SR 95531 binding by interacting with a unique site on the GABAA receptor complex distinct from the sites for 3 alpha, 5 alpha-P, pregnenolone sulfate, GABA, benzodiazepines, and barbiturates.

Allosteric Regulation↗
PubMed1996

Characterization of peripheral benzodiazepine type sites in a cultured murine BV-2 microglial cell line.

It is known that the density of peripheral benzodiazepine receptors (PBR) increases after brain damage. Astrocytes are among the cell types where PBR ligand binding has been detected and may be involved in the response to neuronal injury and regeneration. Consistent with the hypothesis, the apparent density of PBR sites in astrocytes is increased by both cytokines and neurotoxins. However, microglia, the resident macrophages which represent 5-15% of glial cell populations have not been evaluated for the presence of the PBR. In the present study, we report the presence of [3H]Ro5-4864 binding in microglial cells. In particular, we used BV-2 cells, an immortalized cell line of murine microglial cells. High affinity binding of [3H]Ro5-4864 to a single site was detected in membranes prepared from BV-2 cells (KD = 4.4 nM, Bmax = 3,800 fmoles/mg protein). Various ligands for the PBR displaced [3H]Ro5-4864 binding with the following rank order of potencies: PK11195 = Ro5-4864 > FGIN-1-27 > triazolam = diazepam > beta-pro-pyl-beta-carboline-3-carboxylate = clonazepam > lorazepam = flurazepam >> chlordiazepoxide = clorazepate. Subcellular fractionationstudies indicate that the majority of the Ro5-4864 binding sites is in the mitochondrial fraction. The remainder is found in nonmitochondrial cell fractions. The [3H]Ro5-4864 binding observed on intact cells had characteristics similar to those found on membranes. The presence of a high density of PBRs in these cells establish the basis for additional investigations into their possible functional role, if any, in the microglial response to neuronal injury.

Animals↗
PubMed1996

A metabotropic glutamate receptor agonist regulates neurotrophin messenger RNA in rat forebrain.

We have examined the role of metabotropic glutamate receptor activation in regulating neurotrophin messenger RNA levels in the brain with the use of the selective agonist (1S,3R)-1-aminocy-clopentane-1,3-dicarboxylic acid. Intracerebroventricular injection of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid into adult adult rats resulted in increased expression of nerve growth factor and brain-derived neurotrophic factor messenger RNA in the hippocampal and pyriform cortex and decreased levels of neurotrophin-3 messenger RNA in the hippocampal dentate gyrus granule cell layer. C-fos messenger RNA levels were also increased throughout hippocampal and cortical subfields following (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid administration. (1S,3R)-1-Aminocyclopentane-1,3-dicarboxylic acid-induced changes in messenger RNA levels occurred without behavioral seizures, yet these changes were similar in magnitude and time course to early changes in neurotrophin and c-fos messenger RNA levels observed following recurrent limbic seizures. In contrast quisqualate, a potent agonist of metabotropic as well as ionotropic kainate/alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors, was only capable of inducing increased expression of brain-derived neurotrophic factor messenger RNA at doses which produced recurrent motor seizures, and both effects were completely inhibited by the non-N-methyl-D-aspartate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. Neurotrophin messenger RNA changes induced by (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid were also partially susceptible to 6-cyano-7-nitroquinoxaline-2,3-dione antagonism, as well as the specific N-methyl-D-aspartate receptor antagonist (+)-5-methyl-10,11-dihydroxy-5H-dibenzo(a,d)-cyclohepten-5,10- iminedizoleipine. These results suggest that (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid-sensitive metabotropic glutamate receptors can dramatically increase the expression of neurotrophin and c-fos messenger RNAs in rat forebrain without producing significant behavioral trauma and that these influences may involve ionotropic glutamate receptors in certain brain regions.

Animals↗
PubMed1996

Formation of D-serine from L-phosphoserine in brain synaptosomes.

Although glycine has been assumed to be the sole endogenous coagonist at NMDA-associated glycine receptors, recent descriptions of endogenous D-serine in the brain indicate that this assumption is probably not valid. D-Serine is a stereospecific agonist of the NMDA-associated glycine receptor, with an affinity equal to or greater than that of glycine but with no affinity for the strychnine-sensitive glycine receptor. In the current studies, we assessed the levels and metabolic sources of D-serine in rat neocortical synaptosomal preparations. Previous studies have demonstrated that CNS serine and glycine are synthesized de novo primarily via a phosphorylated pathway, originating with the glycolytic intermediate phosphoglycerate. The rate-limiting step in the synthesis of serine is the hydrolysis of phosphoserine by phosphoserine phosphatase (EC 3.1.3.3). In synaptosomal preparations we have demonstrated high endogenous levels of D-serine and the uptake of L-phosphoserine along with its hydrolysis to both L-serine and D-serine, which are preferentially released into the medium. Experiments with both intact and lysed synaptosomal preparations demonstrated hydrolysis of D-phosphoserine to only D-serine and inhibition of hydrolysis by the phosphoserine phosphatase inhibitor 2-amino-3-phosphonopropionic acid (AP3). The lack of stereospecificity for synaptosomal hydrolysis of phosphoserine and the inhibitory actions of AP3 are consistent with the presence of phosphoserine phosphatase in synaptosomes and further indicate that epimerization of serine can occur during or subsequent to the hydrolysis of L-phosphoserine but not D-phosphoserine. In conclusion, these studies demonstrate that phosphoserine phosphatase may be an important enzyme in regulating the steady-state levels of D-serine in neocortical synaptosomes.

Alanine↗
PubMed1995

Separation and quantification of D- and L-phosphoserine in rat brain using N alpha-(2,4-dinitro-5-fluorophenyl)-L-alaninamide (Marfey's reagent) by high-performance liquid chromatography with ultraviolet detection.

D-Serine has recently been described to be present in the brain at high concentrations. However, while prior research has demonstrated that L-phosphoserine is the major precursor of L-serine in the brain, the possible role of D-phosphoserine as the direct precursor of D-serine is unknown. To address this problem, we developed an assay to separate and quantitate D- and L-phosphoserine. A very simple HPLC-UV procedure for the separation and quantification of D- and L-phosphoserine is presented using precolumn derivatization with a chiral reagent, N alpha-(2,4-dinitro-5-fluorophenyl)-L-alaninamide (Marfey's reagent), and a conventional C18 reversed-phase column. The procedure is sensitive to 11 pmol on-column and derivatives are stable for at least two weeks at room temperature. Rat brain regions (cortex, hippocampus, striatum, and cerebellum) were analyzed for the presence of D- and L-phosphoserine. It was determined that the brain regions studied contained exclusively L-phosphoserine.

Alanine↗
PubMed1995

Rapid and sensitive procedure for the separation and quantitation of D- and L-serine in rat brain using gas chromatography-mass spectrometry.

A very simple and rapid GC-MS procedure for the separation and quantitation of D- and L-serine has been developed utilizing a conventional bonded-phase capillary column. The procedure involves initial esterification with isobutanol followed by acylation with the chiral derivatizing reagent S-(-)-N-(heptafluorobutyryl)prolyl chloride (HPC). This procedure requires neither extraction nor clean-up steps and is sensitive to 50 pg on-column. Total time of the procedure is under 3 h and derivatives are stable at room temperature for at least 5 days, making this procedure ideal for automated injections. A simple, one-day synthesis of HPC is described which yields > 99.9% optical purity.

Acylation↗
PubMed1995

The use of the pain drawing as a screening measure to predict psychological distress in chronic low back pain.

STUDY DESIGN: The ability of three new methods of scoring the Pain Drawing to predict psychological distress in two cohorts of 100 patients with chronic low back pain was investigated. OBJECTIVES: Patients completed a Pain Drawing and questionnaire measures of psychological distress and were given a standard physical examination. SUMMARY OF BACKGROUND DATA: The two cohorts were significantly different on all variables (except for disability). METHODS: The relationship between the three new scoring systems and measures of distress, physical factors, and disability was investigated. RESULTS: The new scoring methods had high reliability. Pain Sites was a more accurate predictor of distress, but was unable to do so with sufficient specificity/sensitivity. Body Map did not correlate with physical/disability measures. CONCLUSION: Using the new scoring systems, it was not possible to identify distressed patients with sufficient sensitivity/specificity, nor to differentiate between organic and nonorganic pain patterns.

Chronic Disease↗
PubMed1995

The co-agonist concept: is the NMDA-associated glycine receptor saturated in vivo?

Our current knowledge of the structure and function of NMDA receptors is expanding at a rapid pace; however, advances regarding regulation of the supply of glutamate and its co-agonist, glycine, have been slower. While the anatomical sources and metabolic compartmentation of glutamate have been studied, limited efforts have been dedicated to defining the dynamics and compartmentation of the co-agonist, glycine. In fact, most investigators have made the assumption that glycine is freely available, via diffusion, for synaptic transmission at NMDA-type synaptic clefts. This assumption ignores the intricate inactivation mechanisms potentially involved in regulating synaptic levels of this amino acid and the recent descriptions of high levels of endogenous D-serine, another potential agonist of the NMDA-associated glycine receptor, in the brain. In this review, the relevance of these data and pharmacological experiments pertinent to the question of whether the NMDA-associated glycine receptor is saturated in vivo or not, is presented.

Animals↗
PubMed1995

Microglial cathepsin B: an immunological examination of cellular and secreted species.

The cysteine proteinase cathepsin B (CB) was isolated from immortalized murine BV-2 microglial cells and examined via sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblotting to establish physicochemical properties of CB from what is generally considered the resident CNS macrophage. Microglial proteases have been implicated in several pathological processes occurring in the CNS, including neurodegeneration. Murine microglial CB was observed to consist of two major single-chain species of 32 and 34 kDa, with pls of 5.5-5.2 and 5.1-4.5, respectively. In addition, a minor 24-kDa CB species was also observed in some microglial preparations. The major CB isozymes in microglia differed from those observed in murine liver and brain, which consisted of both single- and double-chain CB variants of 31 and 24-25 kDa/5 kDa, respectively, with pl values of 5.5-4.5. A microglial pro-CB of 37 kDa was also isolated, which could be processed to the 34-kDa single-chain CB species. Cystatin was observed to prevent pro-CB processing, whereas E-64 and leupeptin were only partially inhibitory. The 37-kDa pro-CB species was observed to undergo processing into the 34-kDa CB species when incubated at pH 5.5 but remained stable with respect to molecular mass when incubated at pH 7.0. In contrast, the 34-kDa single-chain CB species was observed to autodegrade when incubated at pH 7.0, whereas incubation at pH 5.5 did not affect the integrity of the species as monitored by immunoblotting. Both pro-CB and 32-kDa single-chain CB species were observed extracellularly following lipopolysaccharide activation of BV-2 microglial cells.

Animals↗
PubMed1995

Microglia as a unique cellular target in the treatment of stroke: potential neurotoxic mediators produced by activated microglia.

The sequalae evoked by an initial ischemic event in the CNS are incredibly complex and involve a wide range of short-term and long-term metabolic adaptations. With regard to the 'penumbra' area, in which cell death occurs over a 1 to 3 day period, defining the roles of potential neurotoxic mediators is crucial. In this regard, upon cellular activation after an ischemic episode, microglia, the resident macrophages of the CNS, can produce large quantities of a number of neurotoxic mediators. These factors include excitatory amino acids, proteases, cytokinases and nitric oxides. In this manuscript, these mediators are reviewed with regard to the potential utility of suppression of microglial function, via immunosuppressive agents, in the treatment of stroke.

Cell Communication↗
PubMed1994

Bilateral changes in striatal dopamine metabolism after unilateral intracarotid and intrastriatal administration of apomorphine.

Following cannulation of the common carotid artery of female Sprague-Dawley rats, 3 microCi (10 micrograms) of [3H]apomorphine were infused. At various time intervals, drug concentrations were determined in the right and left striata, anterior forebrains, posterior forebrains and cerebella. One minute following intracarotid infusion of apomorphine, approximately a 65-fold right/left difference in apomorphine concentrations was attained in all forebrain structures, and this difference steadily diminished with time as a result of declining drug levels in the infused hemisphere. The concentrations of dopamine and its metabolites (DOPAC, HVA and 3-MT) were quantified by gas chromatography-mass spectrometry in the right and left striata at 5 and 15 min after unilateral intracarotid infusion of 1 microgram apomorphine. At both time intervals and regardless of the side infused, the metabolites of dopamine increased ipsilateral to the side of infusion. Moreover, 3-MT levels were significantly decreased in the contralateral striatum. After direct intrastriatal injection of either 0.1 or 1.0 microgram apomorphine into the right striatum, the levels of dopamine metabolites were again increased in the ipsilateral striatum. 3-MT levels were also decreased significantly in the left striatum. In contrast to the effects observed after systemic administration of apomorphine, these results demonstrate that dopamine release in the striatum is increased by selectively delivering higher concentrations of apomorphine to the nerve terminals of the nigrostriatal neurons. The effects of unilateral apomorphine on dopamine metabolism in the contralateral striatum are most likely the effect of interhemispheric communication.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Inducible microglial nitric oxide synthase: a large membrane pool.

Microglia are the only immunocompetent cells resident in the central nervous system which are capable of protecting the brain from infection and tumors. These resident macrophages possess a vast array of mechanisms for the destruction of bacteria and tumor cells. One of these mechanisms involves the generation of nitric oxide which can kill cells by inhibition of glycolysis, the TCA cycle and DNA synthesis. In this regard, we demonstrate, for the first time, that the inducible form of nitric oxide synthase (NOS) in microglia involves both cytosolic and membrane bound pools. Both pools of NOS were potently and stereo-specifically inhibited by NOS inhibitors. In addition, while these pools were unaffected by Ca2+, they were partially inhibited by calmodulin antagonists. These data would suggest that inducible NOS in lipopolysaccharide (LPS) treated microglia, constitutes two major compartments and may involve a novel isoform which is membrane associated. With regard to the possible physiological relevance for the membrane-bound NOS, we speculate that this presents an efficient means of supplying nitric oxide to the extracellular environment where it could gain rapid access to tumors and bacteria. This would result in inhibition of cellular function in these invading cells while limiting access of nitric oxide to the intracellular environment of microglia where NO could lead to depressed microglial function.

Amino Acid Oxidoreductases↗
PubMed1994

Differential regulation of IL-1 alpha and TNF alpha release from immortalized murine microglia (BV-2).

Microglia, the resident macrophages of the brain, secrete a number of mediators involved in neural-immune function. The cytokines, IL-1 alpha and TNF alpha, are two such factors which are stored as inactive precursor molecules requiring post-translational proteolytic processing prior to release. From investigations of second messenger pathways involved in regulating the secretion of these cytokines, we have demonstrated that the PKC inhibitor, H-7, blocks the induction of TNF alpha secretion induced by LPS. In contrast, H-89 and HA-1077, inhibitors of cyclic nucleotide-dependent protein kinases (PKA and PKG), did not alter LPS-stimulation of TNF alpha release. Consistent with these observations, the weak PKC activator, mezerein, induced TNF alpha secretion in an H-7-reversible manner. In marked contrast, PKC activation did not induce IL-1 alpha secretion and H-7 potentiated IL-1 alpha release. In the case of the protein phosphatase inhibitor, okadaic acid, secretion of both cytokines was induced, indicating that protein phosphorylation is important for the induction of cytokine secretion but only in the case of TNF alpha is PKC involved. In the case of IL-1 alpha, a tonic inhibitory regulation involving PKC activation may be present. We therefore conclude that alterations in phosphorylation-dephosphorylation cycles may be important triggers in the switching of microglial cellular function from a resting to an activated state.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗