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PubMed2001

Neuroprotection for ischaemic stroke: an unattainable goal?

Neuroprotective therapies for acute ischaemic stroke have yet to be realised despite the determined efforts of basic science and clinical investigators. Progressive elucidation of the complex pathophysiology involved in the ischaemic cascade has led to the development of numerous candidate interventions. Preliminary efficacy in animal models has repeatedly resulted in frustration after extensive clinical testing. Failure in the translation of results from animal models to humans implicates potential limitations of the current drug development process. Reflection on prior studies suggests possible flaws at several stages. Incorporation of standardised guidelines for preclinical testing of putative neuroprotective therapies and modification of clinical trial design, methodology and reporting may improve chances for success. The future of neuroprotection for stroke remains bright in spite of previous disappointments.

Animals↗
PubMed2001

Replacement therapy with hydrocortisone in catecholamine-dependent septic shock.

Septic shock is one of the leading causes of death in intensive care units world-wide. Scientists have made great improvements in understanding mechanisms of inflammation, and the sequence of activation of the various pro- and anti-inflammatory markers is now well known. In contrast, physicians have failed to improve survival from septic shock despite the development of specific targets at various points in the cytokine cascade considered to have a key role in host survival in sepsis. Corticosteroids were among the first anti-inflammatory drugs to be tested in large randomized controlled trials. These trials showed that patients with septic shock did not benefit from a short course of large doses of steroids. More recent findings highlighting the role of the integrity of the hypothalamic-pituitary-adrenal axis to respond appropriately to a septic insult, have led to a re-appraisal of the use of steroids in septic shock. Several randomized controlled trials have evaluated the efficacy of a replacement therapy with hydrocortisone in severe sepsis. These trials strongly suggest that this replacement therapy reduces the morbidity of septic shock and may favorably affect survival from septic shock.

Animals↗
PubMed1992

Inhibition of equine complement activity by polysulfated glycosaminoglycans.

The ability of polysulfated glycosaminoglycans (PSGAG) to inhibit the complement cascade was evaluated. The role of complement in inflammation and infection has been well documented. Inhibition of the complement cascade by PSGAG could explain why intra-articularly administered PSGAG diminish diarthrodial joint inflammation and potentiate septic arthritis in horses. Hemolytic complement testing was performed to evaluate the effect of PSGAG on the equine classical and alternate pathways of complement, using rabbit erythrocytes as the target cells. Concentration of PSGAG between 0.2 mg/ml and 0.6 mg/ml significantly (P less than 0.05) inhibited equine complement in dose-related fashion. Further increase in complement inhibition was not observed at PSGAG concentration greater than 0.6 mg/ml. Difference was not apparent in the extent of inhibition of complement from each of the 4 horses tested. Polysulfated glycosaminoglycans appeared to inhibit the classical and alternate complement pathways equally, indicating possible effect on complement components common to both pathways. Heat inactivation of complement function completely inhibited (P less than 0.01) the hemolytic activity of the serum from all horses.

Animals↗
PubMed1987

Retinoids as preventive and therapeutic anticancer agents (Part I).

Retinoids, the synthetic and natural analogs of vitamin A, frequently block the phenotypic expression of cancer in vitro; they also inhibit growth and induce differentiation in many animal and human malignant cell types. Only recently has it become possible to propose a unifying mechanism of retinoid action, which involves the protein kinase-C cascade system. This system may mediate retinoids' many diverse actions, including their effects on enzyme synthesis, membrane properties, growth factors, binding proteins, genomic and postgenomic expression, the extracellular matrix, and immunologic responses. Ongoing in vitro studies of retinoid structure-activity relationships, effects on oncogene expression, reversal of drug-resistance, and, especially, the protein kinase-C cascade system should help clarify the precise mechanism of their anticancer action. Many in vitro and in vivo assay systems are available for testing the 2000 + synthetic retinoids. These assays indicate specific drug sensitivities, which may help focus future clinical trials. In human cancer prevention, retinoids have been most effective for skin diseases, including actinic keratosis, keratoacanthoma, and basal cell carcinoma; however, nondermatologic premalignancies, such as oral leukoplakia, bronchial metaplasia, laryngeal papillomatosis, cervical dysplasia, myelodysplastic syndromes, and the urinary bladder, also respond to retinoid therapy. Significant therapeutic advances are also occurring with this class of drugs in refractory malignancies, including advanced cutaneous squamous and basal cell cancer, mycosis fungoides, and acute promyelocytic leukemia. Newer third-generation retinoids, such as the highly potent retinoidal benzoic acid derivatives, are demonstrating therapeutic indexes far higher than earlier-generation retinoids. Current in vitro testing is also demonstrating that retinoids have synergistic activity in combination with other agents (eg, biologic modifiers, hormones, and DNA synthesis inhibitors) and treatment modalities (eg, irradiation). Notwithstanding the progress already made with retinoids in human cancer, many in vitro questions remain, and clinical work is just beginning.

Animals↗
PubMed1995

Pharmacologic therapy: promising clinical investigations.

The identification of ischemia as a central mechanism of cell injury within the nervous system has resulted in a commonality of interests of neurosurgeons, neurologists and basic scientists interested in head injury, subarachnoid hemorrhage and stroke. This, in turn, has led to a certain synergy between the development of new agents and the availability of interested and committed investigators so that these agents can be tested under appropriate clinical conditions. In head injury, major sources of focus have been the membrane damage resulting from the free-radical cascade and the disruption in cellular ionic homeostasis resulting from the excitotoxic effects of pathologic release of amino acid neurotransmitters. At present, the final analyses of phase III trials of the antagonism of the initiation and propagation of the free-radical cascade by tirilazad and polyethylene glycol-bound superoxide dismutase are nearing completion. Data on the efficacy of these agents in improving outcome from moderate and severe head injury should be available within the next 6 months. In addition, worldwide trials of glutamate antagonists are presently being initiated in severe head injury, with results anticipated in late 1997 or early 1998. In subarachnoid hemorrhage, calcium has been hypothesized to play a role in mediating vasospasm-induced ischemia as well as in promoting intracellular damage. Trials of calcium-channel blockade have demonstrated a reduction in mortality, but no improvement in the quality of survival over other methods of managing these patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain Injuries↗
PubMed1993

Role of tyrosine kinase activity in signal transduction by the insulin-like growth factor-I (IGF-I) receptor. Characterization of kinase-deficient IGF-I receptors and the action of an IGF-I-mimetic antibody (alpha IR-3).

The insulin-like growth factor-I (IGF-I) receptor is a member of a large family of transmembrane signal transducing molecules. The defining characteristic of this class of receptors is the intrinsic tyrosine kinase activity of the cytoplasmic domain. While it has been demonstrated that this tyrosine kinase activity is necessary for the action of a number of transmembrane tyrosine kinase receptors, no evidence of this type has been adduced to date with respect to the signaling requirement of the IGF-I receptor. We have now shown that stably transfected NIH-3T3 cell lines overexpressing human IGF-I receptors display increased responses to IGF-I and an IGF-I-mimetic antibody, alpha IR-3, in terms of short, intermediate, and long term actions initiated by activation of the IGF-I receptor. These include receptor autophosphorylation, activation of phosphatidylinositol-3-kinase and 2-deoxyglucose uptake, induction of ornithine decarboxylase gene expression, and stimulation of thymidine incorporation. In short term responses, the kinetics seen with alpha IR-3 were slower than those seen with IGF-I. These effects were severely decreased in clones expressing human IGF-I receptors in which the lysine residue in the ATP-binding site of the tyrosine kinase domain had been mutated to alanine or arginine. This was true for both IGF-I and alpha IR-3. These results indicate that, for all parameters tested, the tyrosine kinase activity of the IGF-I receptor is necessary for activation of the IGF-I-stimulated signal transduction cascade. Additionally, the effects of alpha IR-3 also require tyrosine kinase activity.

3T3 Cells↗
PubMedDate not supplied

[Modern views on etiopathogenesis of Alzheimer's disease].

The aetiology of Alzheimer's disease (AD) remains, despite vast progress, not fully understood. Four genes involved in the development of the disease have been identified. Three fully penetrant ones (the amyloid beta-protein precursor on chromosome 21, presenilin 1 on chromosome 14, and presenilin 2 on chromosome 1) lead to the development of relatively rare familial form of AD. Together, they account for about half of this early-onset form of the disease. One genetic risk factor--polipoprotein E-4--is associated with late-onset Alzheimer's disease while at least two others are proposed. None of these genes can be by now adopted for use as a diagnostic or predictive test for Alzheimer's disease. Apart from the above, some environmental factors are also implicated in pathogenesis of the disease with the amyloid cascade hypothesis being the most commonly accepted as central. In the presented paper we have critically reviewed a literature on etiopatogenesis of Alzheimer's disease and discussed some practical consequences of the progress in understanding the mechanism of the disease.

Amyloid beta-Protein Precursor↗
PubMed2000

Sensitive genetic screen for protease activity based on a cyclic AMP signaling cascade in Escherichia coli.

We describe a genetic system that allows in vivo screening or selection of site-specific proteases and of their cognate-specific inhibitors in Escherichia coli. This genetic test is based on the specific proteolysis of a signaling enzyme, the adenylate cyclase (AC) of Bordetella pertussis. As a model system we used the human immunodeficiency virus (HIV) protease. When an HIV protease processing site, p5, was inserted in frame into the AC polypeptide, the resulting ACp5 protein retained enzymatic activity and, when expressed in an E. coli cya strain, restored the Cya(+) phenotype. The HIV protease coexpressed in the same cells resulted in cleavage and inactivation of ACp5; the cells became Cya(-). When the entire HIV protease, including its adjacent processing sites, was inserted into the AC polypeptide, the resulting AC-HIV-Pr fusion protein, expressed in E. coli cya, was autoproteolysed and inactivated: the cells displayed Cya(-) phenotype. In the presence of the protease inhibitor indinavir or saquinavir, AC-HIV-Pr autoproteolysis was inhibited and the AC activity of the fusion protein was preserved; the cells were Cya(+). Protease variants resistant to particular inhibitors could be easily distinguished from the wild type, as the cells displayed a Cya(-) phenotype in the presence of these inhibitors. This genetic test could represent a powerful approach to screen for new proteolytic activities and for novel protease inhibitors. It could also be used to detect in patients undergoing highly active antiretroviral therapy the emergence of HIV variants harboring antiprotease-resistant proteases.

Adenylyl Cyclases↗
PubMed2005

Association testing of the protein tyrosine phosphatase 1B gene (PTPN1) with type 2 diabetes in 7,883 people.

Protein tyrosine phosphatase (PTP)-1B, encoded by the PTPN1 gene, inactivates the insulin signal transduction cascade by dephosphorylating phosphotyrosine residues in insulin signaling molecules. Due to its chromosomal location under a chromosome 20 linkage peak and the metabolic effects of its absence in knockout mice, it is a candidate gene for type 2 diabetes. Recent studies have associated common sequence variants in PTPN1 with type 2 diabetes and diabetes-related phenotypes. We sought to replicate the association of common single nucleotide polymorphisms (SNPs) and haplotypes in PTPN1 with type 2 diabetes, fasting plasma glucose, and insulin sensitivity in a large collection of subjects. We assessed linkage disequilibrium, selected tag SNPs, and typed these markers in 3,347 cases of type 2 diabetes and 3,347 control subjects as well as 1,189 siblings discordant for type 2 diabetes. Despite power estimated at >95% to replicate the previously reported associations, no statistically significant evidence of association was observed between PTPN1 SNPs or common haplotypes with type 2 diabetes or with diabetic phenotypes.

Base Sequence↗
PubMed2004

Combination therapy for multiple sclerosis.

To improve the partial benefit of approved monotherapies in multiple sclerosis (MS), over 25 combined therapies have been tested in recent years, either as fixed-dose or sequential combination regimes. The main therapeutic targets for combination therapy in MS are the same as for monotherapy: the immune-mediated inflammatory cascade, oxidative toxicity and excitotoxicity. There are numerous reasons to consider combination therapy in MS, including to improve the benefit and/or tolerance in patients responding to approved treatments, stop frequent disabling relapses and/or rapid progression in patients who do not respond to approved therapies, and maintain the benefit of immunosuppressive treatments. Preliminary clinical trials suggest that combination therapy in MS does not increase the side-effects of approved monotherapy; its efficacy over monotherapy should therefore be tested. Statistically robust trials would need to involve many patients for each combination, so the first step in determining the efficacy of combination therapy should be to perform safety studies, followed by proof-of-concept efficacy studies.

Clinical Trials as Topic↗
PubMedDate not supplied

Role of biosurfactant and ion channel-forming activities of syringomycin in transmembrane ion flux: a model for the mechanism of action in the plant-pathogen interaction.

Syringomycin is a necrosis-inducing lipopeptide toxin synthesized and secreted by the phytopathogen, Pseudomonas syringae pv. syringae. Although small quantities of syringomycin are known to activate a cascade of physiological events in plasma membranes, the mechanism of action of the phytotoxin has never been fully characterized. The objective of this study was to test the hypothesis that the primary mode of action of syringomycin is to form transmembrane pores that are permeable to cations. Accordingly, direct measurement of ion fluxes were performed using artificial bilayers. The hemolytic properties and surface activity of HPLC-purified syringomycin were quantified by use of an erythrocyte lysis assay and by the drop weight method. Assays were performed using syringomycin form SRE alone or a mixture containing all forms of the phytotoxin. At a threshold concentration of 500 ng/ml, syringomycin induced hemolysis by forming ion channels in membranes. Osmotic protection studies indicated a channel radius of between 0.6 and 1 nm. The ion channel-forming activity was insensitive and permeable to both monovalent and divalent cations, suggesting that syringomycin causes lysis of erythrocytes by colloid osmotic lysis. In addition, syringomycin, like other lipopeptide antibiotics, is a potent biosurfactant capable of lowering the interfacial tension of water to 31 mN/m. The critical micellar concentration of syringomycin was calculated to be 1.25 mg/ml and the gamma CMC was 33 mN/m. A model is presented depicting the mechanism of action of syringomycin in the plant-pathogen interaction. The model integrates known effects of the toxin on ion flux in plasma membranes with formation of ion channels and the consequential cascade of effects associated with cellular signalling.

Amino Acid Sequence↗
PubMed1999

POG1, a novel yeast gene, promotes recovery from pheromone arrest via the G1 cyclin CLN2.

In the absence of a successful mating, pheromone-arrested Saccharomyces cerevisiae cells reenter the mitotic cycle through a recovery process that involves downregulation of the mating mitogen-activated protein kinase (MAPK) cascade. We have isolated a novel gene, POG1, whose promotion of recovery parallels that of the MAPK phosphatase Msg5. POG1 confers alpha-factor resistance when overexpressed and enhances alpha-factor sensitivity when deleted in the background of an msg5 mutant. Overexpression of POG1 inhibits alpha-factor-induced G1 arrest and transcriptional repression of the CLN1 and CLN2 genes. The block in transcriptional repression occurs at SCB/MCB promoter elements by a mechanism that requires Bck1 but not Cln3. Genetic tests strongly argue that POG1 promotes recovery through upregulation of the CLN2 gene and that the resulting Cln2 protein promotes recovery primarily through an effect on Ste20, an activator of the mating MAPK cascade. A pog1 cln3 double mutant displays synthetic mutant phenotypes shared by cell-wall integrity and actin cytoskeleton mutants, with no synthetic defect in the expression of CLN1 or CLN2. These and other results suggest that POG1 may regulate additional genes during vegetative growth and recovery.

Cyclins↗
PubMed2006

PARP inhibition prevents postinfarction myocardial remodeling and heart failure via the protein kinase C/glycogen synthase kinase-3beta pathway.

The inhibition of glycogen synthase kinase-3beta (GSK-3beta) via phosphorylation by Akt or protein kinase C (PKC), or the activation of mitogen-activated protein kinase (MAPK) cascades can play a pivotal role in left ventricular remodeling following myocardial infarction. Our previous data showed that MAPK and phosphatidylinositol-3-kinase/Akt pathways could be modulated by poly(ADP-ribose)polymerase (PARP) inhibition raising the possibility that cardiac hypertrophic signaling responses may be favorably influenced by PARP inhibitors. A novel PARP inhibitor (L-2286) was tested in a rat model of chronic heart failure following isoproterenol-induced myocardial infarction. Subsequently, cardiac hypertrophy and interstitial collagen deposition were assessed; additionally, mitochondrial enzyme activity and the phosphorylation state of GSK-3beta, Akt, PKC and MAPK cascades were monitored. PARP inhibitor (L-2286) treatment significantly reduced the progression of postinfarction heart failure attenuating cardiac hypertrophy and interstitial fibrosis, and preserving the integrity of respiratory complexes. More importantly, L-2286 repressed the hypertrophy-associated increased phosphorylation of panPKC, PKC alpha/betaII, PKC delta and PKC epsilon, which could be responsible for the activation of the antihypertrophic GSK-3beta. This work provides the first evidence that PARP inhibition beneficially modulates the PKC/GSK-3beta intracellular signaling pathway in a rat model of chronic heart failure identifying a novel drug target to treat heart failure.

Animals↗
PubMed1997

The Drosophila dCREB-A gene is required for dorsal/ventral patterning of the larval cuticle.

We report on the characterization of the first loss-of-function mutation in a Drosophila CREB gene, dCREB-A. In the epidermis, dCREB-A is required for patterning cuticular structures on both dorsal and ventral surfaces since dCREB-A mutant larvae have only lateral structures around the entire circumference of each segment. Based on results from epistasis tests with known dorsal/ventral patterning genes, we propose that dCREB-A encodes a transcription factor that functions near the end of both the DPP- and SPI-signaling cascades to translate the corresponding extracellular signals into changes in gene expression. The lateralizing phenotype of dCREB-A mutants reveals a much broader function for CREB proteins than previously thought.

Animals↗
PubMed2000

A novel approach using an attenuated recombinant vaccinia virus to test the antipoxviral effects of handsoaps.

Evidence indicates an increase in nosocomial and household infections due to viruses (Jeffries, D.J., 1995. Viral hazards to and from health care workers. J. Hosp. Infect. 30, 140-155). An antiviral assay was developed for evaluating efficiency of handsoaps at inactivating cell-free and cell-associated virus. A recombinant vaccinia virus, lacking a virulence factor (Isaacs, S.N., Kotwal, G.J., Moss, B., 1992. Vaccinia virus complement-control protein prevents antibody-dependent complement-enhanced neutralization of infectivity and contributes to virulence. Proc. Natl. Acad. Sci. USA 89, 628-632), whose construction was described earlier (Kotwal, G.J., Isaacs, S.N., McKenzie, R., Frank, M.M., Moss, B., 1990. Inhibition of the complement cascade by the major secretory protein of vaccinia virus. Science 250, 827-830), was used as the representative poxvirus. Two antibacterial handsoaps, one surgical handsoap, one moisturizing handsoap, and a sanitizing agent were tested. An aliquot of the virus was mixed and incubated with soap, then titrated onto BSC-1 cells for incubation at 37 degrees C for 48 h. The soaps' effect on cell-associated virus was tested similarly. The antibacterial soaps inactivated all cell-free virus in 1 min. The surgical soap was effective with a 5-min incubation. None of the soaps eliminated all of the cell-associated virus in 1 min. This safe and reproducible assay seems efficient to establish the comparative efficacy of household and surgical soaps.

Anti-Infective Agents↗
PubMed1999

Cortical ablation induces a spreading calcium-dependent, secondary pathogenesis which can be reduced by inhibiting calpain.

Many forms of acute brain injury are associated with a secondary, glutamate- and calcium-dependent cascade which greatly exacerbates the final damage. The calcium-dependent protease, calpain, has been implicated as an important variable in this pathogenic process. The present studies tested (i) if similar secondary degeneration occurs following surgical ablation of a discrete area within rat visual cortex, (ii) if activation of calpain contributes to the secondary degeneration by spreading into areas adjacent to the ablation, and (iii) if blocking calpain's proteolytic effects reduces the secondary degeneration attendant to the lesion. Antibodies selective for a protein fragment specifically generated by calpain were used to map areas in which the protease had been activated. Labeling was present 5 min after surgery in a narrow zone surrounding the ablated region. The volume of the immunopositive staining increased twofold within 24 h and fivefold by 48 h, at which time it was equivalent in size to the original lesion. This staining pattern significantly decreased in size at 5 days postsurgery. Application of calpain inhibitors to the ablation site immediately after surgery reduced the spread of calpain activation by approximately 80%. Following cortical ablation, the volume of the lateral geniculate nucleus ipsilateral to the cortical ablation shrank by 46 +/- 3% in control rats but only by 31 +/- 5% in animals given the calpain inhibitors. These results establish that (i) a secondary degenerative cascade is unleashed following discrete cortical surgery which expands into brain areas clearly outside the initial perturbation site, (ii) the gradual expansion of calpain activation contributes to the underlying secondary pathology, and (iii) blocking calpain activity substantially reduces atrophy in areas anatomically connected, but physically distal to the damaged zone. The possible utility of topical applications of calpain inhibitors, or analogously acting drugs, in minimizing the secondary effects of brain surgery is discussed.

Animals↗
PubMed1995

Delivery of glucocorticoids by jet nebulization: aerosol characteristics and output.

BACKGROUND: Since inflammation has been identified as a critical factor in the pathogenesis of asthma, use of inhaled glucocorticoids has increased. Because young children are often unable to coordinate properly the use of metered-dose inhalers and no glucocorticoids preparations for nebulization have been approved in the United States, parenteral and intranasal glucocorticoids preparations are occasionally administered by nebulization. METHODS: We examined whether a parenteral preparation (triamcinolone acetonide [TAA]; Kenalog) could be delivered by nebulization. TAA, 1000 micrograms (0.1 ml), was placed in the nebulizer bowl (MB5 [MeFar, Brescia, Italy] or Pari-Jet [Dura Pharmaceuticals, San Diego, Calif.]), then diluted with 2.9 ml normal saline solution for a total volume fill of 3 ml. Using a laser particle analyzer, high-performance liquid chromatography, and cascade impactor, we examined the percentage of aerosol volume produced with particles in the respirable range of 1 to 5 microns in diameter, actual TAA output (in micrograms) and concentration of TAA contained in the particles within the respirable range. RESULTS: Laser particle analysis indicated that 34% +/- 3% (mean +/- SEM) (MB5) and 47 +/- 3% (Pari-Jet) of the total aerosol volume produced were within the respirable range of 1 to 5 microns in diameter, and this remained consistent throughout nebulization. The nebulizer was stopped serially for determination of TAA output with high-performance liquid chromatography. TAA output (1000 micrograms less the amount in micrograms remaining after nebulization) was essentially complete after 2 minutes with the Pari-Jet and within 4 minutes with the MB5 and totaled 352 +/- 19 micrograms and 367 +/- 9 micrograms, respectively. Finally, cascade impactor studies confirmed that 33.4% of the TAA aerosol generated by the MB5 nebulizer was contained in particles in the respirable range. CONCLUSION: Approximately 35% (Pari-Jet) and 37% (MB5) of the initial 1000 micrograms of TAA was delivered with the two nebulizers tested. The particles generated within the respirable range were limited to 34% (MB5) and 47% (Pari-Jet) of the amount delivered. TAA was equally distributed in the particles generated. The theoretic amount delivered in the respirable range was approximately 12.5% for the MB5 nebulizer on the basis of the cascade impactor and 16.5% for the Pari-Jet (assuming TAA distribution equivalence) of the TAA placed in each of the nebulizers. Additional clinical studies are needed to define efficacy and safety in view of the excipients used in preparing the parenteral preparation.

Aerosols↗
PubMed1998

Nonobligate role of early or sustained expression of immediate-early gene proteins c-fos, c-jun, and Zif/268 in hippocampal mossy fiber sprouting.

Axon sprouting in dentate granule cells is an important model of structural plasticity in the hippocampus. Although the process can be triggered by deafferentation, intense activation of glutamate receptors, and other convulsant stimuli, the specific molecular steps required to initiate and sustain mossy fiber (MF) reorganization are unknown. The cellular immediate early genes (IEGs) c-fos, c-jun, and zif/268 are major candidates for the initial steps of this plasticity, because they encode transcription factors that may trigger cascades of activity-dependent neuronal gene expression and are strongly induced in all experimental models of MF sprouting. The mutant mouse stargazer offers an important opportunity to test the specific role of IEGs, because it displays generalized nonconvulsive epilepsy and intense MF sprouting in the absence of regional cell injury. Here we report that stargazer mice show no detectable elevations in c-Fos, c-Jun, or Zif/268 immediate early gene proteins (IEGPs) before or during MF growth. Experimental results in stargazer, including (1) a strong IEGP response to kainate-induced convulsive seizures, (2) no IEGP response after prolongation of spike-wave synchronization, (3) no IEGP increase at the developmental onset of seizures or after prolonged seizure suppression, and (4) unaltered levels of the intracellular Ca2+-buffering proteins calbindin-D28k or parvalbumin, exclude the possibility that absence of an IEGP response in stargazer is either gene-linked or suppressed by known refractory mechanisms. These data demonstrate that increased levels of these IEGPs are not an obligatory step in MF-reactive sprouting and differentiate the early downstream molecular cascades of two major seizure types.

Animals↗