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PubMed1987

Pro-convulsant actions of theophylline and caffeine in the hippocampus: implications for the management of temporal lobe epilepsy.

The pro-convulsant actions of theophylline and caffeine have been investigated using the hippocampal slice preparation and rats administered kainic acid or Metrazol. Both theophylline and caffeine induced the generation of epileptiform activity in the CA3 region of the hippocampal slice with convulsive dose50 (CD50) values of 3 microM respectively. Kainic acid-induced bursting in hippocampal slices was enhanced by theophylline (0.3-30 microM) and caffeine (1-100 microM). Theophylline induced burst firing in response to electrical stimulation in hippocampal area CA3 but not area CA1. Theophylline (50 mg/kg) strongly potentiated the effect of the limbic convulsant kainic acid in vivo whilst a dose of 200 mg/kg was necessary to significantly lower the threshold dose of Metrazol required to induce generalized convulsions. We conclude that alkylxanthines, probably by antagonizing the effect of endogenous adenosine, exert a pro-convulsant action in the hippocampus which preferentially promotes limbic seizures.

Animals↗

PubMed1980

Blockade of cortical spreading depression in electrically and chemically stimulated areas of cerebral cortex in rats.

Penetration of cortical spreading depression (SD) into epileptic foci established in the cerebral cortex by penicillin or Metrazol and into electrically stimulated cortical regions was studied in anaesthetized rats. SD suppressed the activity of penicillin foci with low rates of interictal discharge (0.3 Hz) but did not invade more active foci (1 Hz) or foci triggered by electrical stimulation (1-3 Hz). Metrazol foci did not block SD propagation unless stimulated at 6-10 Hz. Repetitive direct cortical responses elicited by 0.05-0.1 msec pulses blocked SD propagation when applied at 6-10 Hz for 5-20 min. The SD blockade covered an area 3-5 mm in diameter around the bipolar stimulating electrodes. The block outlasted the stimulation for several minutes but was fully reversible. New stimulation reinstated the SD blockade after a shorter latency and at lower stimulus intensities and rates. Interaction of the blocked cortical area and SD resulted in anomalous SD propagation, characterized by reentry or circle waves, returning through or around the stimulated region to the recovered cortex. The dynamics of the onset and offset of blocking suggests that SD propagation is prevented by enhanced K+ reabsorption which rapidly removes the K+ ions penetrating the stimulated area from the SD wave front. The interactive phenomena, particularly SD circulation around an epileptic focus, may account for periodic changes of ictal and interictal activity found in some types of focal epilepsy.

Animals↗

PubMed1984

Morphine responsiveness and seizure proneness.

Previous research demonstrated that following amygdala kindling, animals showed a heightened sensitivity to morphine's convulsive effects and an exaggerated Straub tail response. These effects were evident to 3 months after their last convulsion and could be blocked by naloxone pretreatment. The present paper extends these findings by demonstrating that animals given metrazol or electroshock (ECS) convulsions also showed an enhanced morphine response that was blocked by naltrexone. Both metrazol- and ECS-treated animals convulsed in response to doses of morphine that produced little or no effect in control animals. In addition, it was shown that brain damage induced by electrode implantation or neocortex penetration by skull screws also increased an animal's sensitivity to morphine even in the absence of prior convulsions. This effect, however, could not be blocked by naltrexone. Finally, as opiate receptors vary with the diurnal rhythm, we determined that following amygdala kindling, animals are more sensitive to morphine's convulsive action during their dark phase when receptor number and sensitivity are highest. The results indicated that seizure proneness, whether induced by a history of prior convulsions or brain damage, increased sensitivity to morphine. This effect may be due to a change in opiate receptors only when prior convulsions have occurred.

Amygdala↗

PubMed1984

Antiepileptic effects of amphetamine may require GABA (benzodiazepine) activity.

Secondary components of visual evoked potentials (slow negative wave-SNW, and photically-evoked sensory after discharge-SAD) are known to be precursors of experimentally activated wave-spike discharges, similar to wave-spikes of petit mal epilepsy. Both SNW and SAD may be potently suppressed either by amphetamine or GABAergic compounds such as diazepam and sodium valproate. A hypothesis was tested in the present study, that amphetamine-induced suppression of wave-spike discharges may require GABA-benzodiazepine activity for its expression. Electrocortical activity was recorded and averaged in unrestrained albino rats with chronically implanted epicortical electrodes. SNW and SAD obtained in habituated rats in the predrug state were potently suppressed by amphetamine (1 mg/kg, i.p.). Fifteen minutes after amphetamine injection, a challenging drug (metrazol, picrotoxin, convulsant benzodiazepine, Ro 5-3663, or imidazodiazepine, Ro 15-1788) was administered intraperitoneally. Subconvulsive doses of metrazol (10 mg/kg) reversed amphetamine suppression; imidazodiazepine (20 mg/kg) and picrotoxin (1.5 mg/kg) reliably opposed the SNW suppression; convulsant benzodiazepine, Ro 5-3663 (2 mg/kg), showed modest and nonsignificant effect in the same direction. It is proposed that the antiepileptic potency of amphetamine may be associated with its ability, apparently via modulatory effect of norepinephrine, to facilitate the activation of benzodiazepine-GABA receptors.

Amphetamine↗

PubMed1990

Excitatory amino acid antagonists and pentylenetetrazol-induced seizures during ontogenesis. I. The effects of 2-amino-7-phosphonoheptanoate.

The anticonvulsant action of 2-amino-7-phosphonoheptanoate (AP7) was assessed during ontogenesis of the rat. Animals of five age groups (7, 12, 18, 25, and 90 days) were pretreated with AP7 i.p. in the doses from 15 to 60 mg/kg 30 min prior to pentamethylenetetrazol (PTZ; metrazol; 100 mg/kg s.c.). The incidence and latency of minimal seizures (pure clonic without the loss of righting ability) and of generalized tonic-clonic seizures (major) were evaluated and compared with the control groups. Minimal metrazol seizures were not regularly observed in controls between ages 7 and 12 days. An increased incidence was noticed in AP7-treated groups. In animals of 18 days of age and older the AP7-pretreatment did not influence incidence of minimal seizures; the latencies were significantly lengthened only in 18-day-old animals. Major seizures were significantly suppressed with the highest dose of AP7 (60 mg/kg) in all groups except 7-day-old rats. In 90-day-old rats all doses of AP7 were effective in the suppression of major seizures. The latencies of major seizures were increased in 7 and 18 days old rats. It appears that the blockade of NMDA receptor substantially influences the major seizures induced by PTZ, whereas minimal (clonic) seizures are affected weakly. This suggests an important role of NMDA receptor-mediated transmission in the genesis of generalized tonic-clonic seizure pattern.

2-Amino-5-phosphonovalerate↗

PubMedDate not supplied

Effect of daily saline, drug or blank injections on the susceptibility to the convulsant effect of drugs.

The daily intraperitoneal injection to rats of doses of metrazol (30 mg/Kg), strychnin sulfate (1 mg/Kg) or picrotoxin (1.2 mg/Kg) that were initially subconvulsant, caused after a number of days which varied with the drug, clonic convulsions in a high percentage of the animals. However, after 18 daily injections of saline there was a similar increase of seizure susceptibility to the 3 drugs. The daily handling of rats as for injection, either followed or not by actual abdominal pricking (blank injection), had a similar though less pronounced effect. In animals that were housed in the same room where the others were tested, but which were not handled, the above mentioned doses of metrazol, strychnine and picrotoxin had no convulsant effect. These results indicate that the procedure of submitting rats to daily intraperitoneal injections is not as unconsequential as is usually thought to be, and that it may induce neurological changes.

Animals↗

PubMed1978

Differential effects of convulsants on visually evoked responses in the albino rat.

Visually evoked responses (VERs) were recorded from primary visual cortex in unanesthetized albino rats during pharmacological modulation by one of the following convulsant agents: Physostigmine, picrotoxin, strychnine and Metrazol. The data were analyzed in terms of effects on VER components. The rat VER consists of six distinct waves constituted by three positive peaks (P1--P3) and three negative peaks (N1--N3). Results indicate a differential convulsant action on VER components. The administration of picrotoxin, resulted in a suppression of the peak amplitude of P1--N1 and delayed peak latencies of all components. Strychnine reliably shortened P1, N1 and P2 peak latencies, significantly increased N3 peak latency and only suppressed P3--N3 amplitude. Physostigmine essentially suppressed all component amplitudes but only increased peak latencies for P2 and P3 components. Metrazol, in general, was found to be relatively ineffective in the alteration of any VER component in a systematic manner. The data are discussed in terms of differential modes of convulsant action on the visual system. The results are likewise discussed with respect to their implications for convulsant modulation of photically evoked after-discharges.

Animals↗

PubMed1985

Effects of caffeine and chlor-desmethyldiazepam on fighting behavior of mice with different reactivity baselines.

The effects of various doses of caffeine and of chlor-desmethyldiazepam on footshock-induced aggressive behavior were examined in mice with different baselines of aggressiveness. Caffeine significantly increased the number of fighting episodes with all the doses tested. This was more evident in mice with low rather than in those with high basal rates of agonistic response. Caffeine caused the appearance of minimal convulsive signs in mice subjected to a threshold electroshock which did not produce any seizure in the controls; it also increased metrazol toxicity. Chlor-desmethyldiazepam enhanced fighting behavior at doses of 0.04 and 0.08 mg/kg, but decreased it at 1.25 mg/kg. The first two doses produced the same effects as caffeine on electroshock test, but did not influence metrazol toxicity.

Aggression↗

PubMed1985

Toxicity and neuropharmacology of cyclopiazonic acid.

Cyclopiazonic acid (CPA) was found to have many pharmacological properties in common with the antipsychotic drugs chlorpromazine and reserpine. Thus, in mice CPA at ip doses of 5-14 mg/kg body weight produced hypokinesia, hypothermia, catalepsy, ptosis, sedation without loss of righting reflex, tremor, gait disturbance, dyspnoea, opisthotonus, atypical convulsion and prolonged barbiturate-induced sleep. The ip LD50 of CPA was found to be 13 +/- 0.05 mg/kg. The tremors induced by near-lethal doses of CPA were associated with voluntary or forced movements (action tremors); they worsened during the days following treatment, but they were weak compared with the exhausting and continuous tremors of the whole body caused by 20 mg tremorine/kg (used for comparison). When death occurred only 24-259 min after administration of CPA (11-14 mg/kg), it was preceded by dypsnoea, cyanosis, opisthotonus and clonic leg movements and tonic extension of hind legs (convulsions). When death was delayed (2-6 days after CPA administration), it was preceded by prostration, ptosis, hypothermia, tremor and cessation of food and water intake resulting in cachexia; convulsions were not seen in this group of mice. CPA did not affect the rate of convulsion or death caused by either maximal electroshock or metrazol administration but it did delay the onset of metrazol-induced seizures. In rabbits, 10 mg CPA/kg body weight initially produced tachycardia, tachypnoea and sedation with an activated electroencephalogram. Of three rabbits given 10 mg CPA/kg one died, and in this rabbit slow delta waves were seen just before and during a brief period with clonic leg movements. In this animal death was accompanied by tonic extension of the hind legs, respiratory arrest and cardiac fibrillation; and epileptiform EEG was not seen at any time. The unexpected EEG activation with sedation in rabbits treated with CPA was similar to the effect of reserpine on EEG.

Animals↗

PubMed1985

Amplification by glycine of the anticonvulsant effect of THPO, a GABA uptake inhibitor.

THPO, a GABA uptake inhibitor, when given in doses of up to 4 mmol/kg (i.p.) to mice, had only a marginal protective effect against seizures induced 1 hr later by 3-mercaptopropionic acid (MPA). THPO (4 mmol/kg), when given in combination with 10 mmol/kg of glycine, protected 60% of the mice from MPA-induced convulsions. The combination of THPO and glycine delayed the onset of metrazol-induced clonic convulsions and protected 30% of the animals from seizures, although neither glycine or THPO alone had a significant anticonvulsant effect against metrazol induced seizures. In agreement with earlier findings, the results presented in this work seem to indicate that the synergistic anticonvulsant effects of glycine and GABAergic agents are independent of their mode of action: the effects of GABA agonists (muscimol) GABA-T inhibitors (vinylGABA), or an inhibitor of glial GABA uptake (THPO) are similarly amplified by glycine.

3-Mercaptopropionic Acid↗

PubMed1993

Characterization of the anticonvulsant properties of F-721.

The anticonvulsant properties of F-721 (3-diethylamino-2,2-dimethylpropyl-5-[p-trifluoromethylphenyl]-2-f uroate hydrochloride) were investigated in a battery of in vivo and in vitro anticonvulsant model systems. After intraperitoneal (ip) administration in mice, F-721 was effective in nontoxic doses against maximal electroshock (MES), subcutaneous picrotoxin clonic, intracerebroventricular (icv) N-methyl-D-aspartate (NMDA) tonic, icv NMDA clonic and icv quisqualic acid tonic seizures (ED50s: 11.1, 28.4, 1.76, 3.4, and 4.4 mg/kg, respectively). F-721 exhibited only partial activity against clonic seizures induced in the subcutaneous Metrazol and subcutaneous bicuculline test in mice and was inactive in this species against tonic seizures induced in the subcutaneous strychnine test. F-721 was effective against MES seizures following oral administration to mice (ED50: 31.3 mg/kg) and only partially effective by this route against clonic seizures induced by subcutaneous Metrazol. In rats, F-721 was a potent anticonvulsant in the maximal electroshock model following oral administration (ED50: 9.9 mg/kg). F-721 was also effective against corneal-kindled and amygdaloid-kindled seizures in rats. F-721 suppressed stage 5 seizures in corneal-kindled rats with an ED50 of 15 mg/kg, ip. In addition, it also decreased the afterdischarge duration and behavioral seizure stage in amygdaloid-kindled rats at doses that did not cause sedation or ataxia. At 40 mg/kg, F-721 reduced afterdischarge duration by 83.2% and reduced the seizure severity score to 1.7. The ED50 for 50% reduction of afterdischarge duration was 16.3 mg/kg, ip. In cultured mouse spinal cord neurons, F-721 suppressed sustained repetitive firing in response to a depolarizing current with a median inhibitory concentration (IC50) of 1.9 microM. F-721 had no effect on adenosine uptake, gamma-aminobutyric acid or NMDA receptor binding. Comparative data from previous studies with clinically established antiepileptic agents reveal that F-721's profile of activity most closely resembles that of phenytoin and carbamazepine. However, F-721 was notably more efficacious in suppressing amygdaloid-kindled seizures in rats and was a more potent antagonist of icv NMDA clonic seizures. Our studies indicate that F-721 is a potent, orally active anticonvulsant with a favorable margin of safety. The profile of anticonvulsant activity of F-721 suggests potential utility in the management of generalized tonic-clonic, simple and complex partial seizures.

Adenosine↗

PubMed1997

The effect of lactation on induced Fos-like immunoreactivity in the rat hypothalamic paraventricular nucleus.

Lactating rats display a period of blunted hypothalamo-pituitary-adrenal (HPA) response to a variety of stressors. This hyporesponsiveness is reported to be dependent upon continuous mother-pup interactions. In this study, computer-assisted densitometric methods were used to measure levels of induced Fos-like immunoreactivity (FLI) in the hypothalamic paraventricular nucleus (PVN) of lactating and non-lactating rats. Adrenalectomy (ADX) induces elevated levels of FLI in the PVN of non-lactating rats. We have observed that, between post-partum day (pd) 4 and pd 21, the level of ADX-induced FLI in the PVN of lactating rats follows a U-shaped distribution; that the persistence of this phenomenon is dependent upon continued mother-pup interaction and that sustained mother-pup interaction beyond the end of the normal suckling period (pd 21) does not extend the period of refractoriness. We have further determined that both the non-specific neural activator Metrazole, and the glutamate agonist N-methyl-D,L-aspartate (NMA), induced smaller increases in FLI in the PVN of lactating rats compared to non-lactating cohorts, and that the suppressing effect of lactation on Metrazole-induced FLI does not extend to all brain regions. These results suggest that mechanisms responsible for the onset and maintenance of the so-called lactational stress-hyporesponsive period (LSHRP) include altered function of glutamatergic pathways.

Adrenalectomy↗

PubMed1983

Differential rearing affects responsiveness of rats to depressant and convulsant drugs.

The effects of postweaning housing in environmental complexity (EC) or isolation cage (IC) conditions upon the development of anesthesia following sodium pentobarbital administration and upon seizure susceptibility following metrazol administration were studied in separate groups of rats. Male and female EC rats lost the righting reflex and developed unconsciousness more rapidly following sodium pentobarbital injection (105 mg/kg, IP) than did littermate IC rats. Male EC and IC rats did not differ in the CD50 (50% convulsion dosage by log probit analysis) following injection of a range of metrazol doses (20 to 35 mg/kg, IP) when they were kept in a quiet dimly lighted room. However, the addition of stroboscopic light stimulation (1-100 Hz) to the above procedure (doses 17.5 to 30 mg/kg) reduced the CD50 for the IC rats but did not affect the CD50 for the EC rats. The results support the view that brain excitability is lower in animals reared in environments providing higher levels of sensory stimulation.

Animals↗

PubMed2000

Low-temperature crystal structures of tetrakis-mu-3,5-diisopropylsalicylatobis-dimethylformamidodico pper(II) and tetrakis-mu-3,5-diisopropylsalicylatobis-diethyletheratodicopp er(II) and their role in modulating polymorphonuclear leukocyte activity in overcoming seizures.

Two binuclear copper(II) complexes of 3,5-diisopropylsalicylic acid were characterized by single crystal X-ray diffraction methods and examined for anti-inflammatory activity using activated polymorphonuclear leukocytes and for anticonvulsant activities using electroshock and metrazol models of seizures. These complexes were crystallized from dimethylformamide (DMF) or diethylether. Tetrakis-mu-3,5-diisopropylsalicylatobis-dimethylformamidodicop per(II) [Cu(II)2(3,5-DIPS)4(DMF)2] I is in space group P 1; a = 10.393 (2), b = 11.258 (2), c = 12.734 (2) A, alpha = 96.64 (2), beta = 92.95 (2), gamma = 94.90 (2) degrees; V = 1471.7 (4) A3; Z = 1. Tetrakis-mu-3,5-diisopropylsalicylatobis-etheratodicopper(II ) [Cu(II)2(3,5-DIPS)4(ether)2] II is in space group P 1; a = 10.409 (3), b = 11.901 (4), c = 12.687 (6) A, alpha = 91.12 (5), beta = 90.84 (5), gamma = 100.90 (4) degrees; V = 1542 (1) A3; Z = 1. The structure of I was determined at 140 K from 4361 unique reflections (I > 2sigma(1)) and refined on F2 to R1 = 0.04 and wR2 = 0.09. The structure of II was determined at 180 K from 4605 unique reflections (I > 2sigma(I)) and refined on F2 to R1 = 0.05 and wR2 = 0.13. Each compound is a crystallographically centrosymmetric binuclear complex with Cu atoms bridged by four 3,5-diisopropylsalicylate ligands related by a symmetry center [Cu-Cu(i): 2.6139 (9) A in I and 2.613 (1) in II]. The four nearest O atoms around each Cu atom form a nearly rectangular planar arrangement with the square pyramidal coordination completed by the dimethylformamide (or diethylether) oxygen atom occupying an apical position, at a distance of 2.129 (2) A in I and 2.230 (3) A in II. Each Cu atom is displaced towards the DMF (or diethylether) ligand, by 0.189 A in I and 0.184 A in II, from the plane of the four O atoms. The crystal structures of I and II are essentially similar to each other, except for the DMF or diethylether accommodation. Many disorder phenomena were found in the crystal structure of I. Copper(II)2(3,5-DIPS)4(DMF)2 inhibited polymorphonuclear leukocyte (PMNL) oxidative metabolism in vitro. This effect was concentration related and significant for concentrations higher than 10 microg or 0.68 nmol/ml. Copper(II)2(3,5-DIPS)4(DMF)2 was more active than the parent ligand, 3,5-DIPS, as has been demonstrated with copper complexes of other non-steroidal anti-inflammatory drugs. The DMF and diethylether ternary complexes of Cu(II)2(3,5-DIPS)4 were found to have anticonvulsant activity in the maximal electroshock model of grand mal epilepsy in doses ranging from 26 to 258 micromol/kg of body mass following intraperitoneal, subcutaneous, or oral treatment. The DMF ternary complex was also found to be effective in the subcutaneous injection of metrazol model of petit mal epilepsy. We conclude that both ternary copper complexes are lipophilic and bioavailable, capable of facilitating the inflammatory response to brain injury and causing the subsidence of this response in bringing about remission of these disease states.

Animals↗

PubMed2002

Synthesis, crystal structure, EPR properties, and anti-convulsant activities of binuclear and mononuclear 1,10-phenanthroline and salicylate ternary copper(II) complexes.

Two ternary Cu(II) complexes of 1,10-phenanthroline (phen) and singly (Hsal(-)) or dideprotonated (sal(2-)) salicylate ligands were synthesized, their X-ray crystal structure and electron paramagnetic resonance spectral characteristics determined, and evaluated for anti-convulsant activities in the maximal electroshock (MES) and Metrazol models of seizure and Rotorod toxicity. The X-ray crystal structure of [bis(1,10-phenanthroline)-mu-bis(salicylato-O,O')dicopper(II)] dihydrate, 1, ([Cu(II)(2)(phen)(2)(sal)(2)].2[H(2)O]), shows it to be binuclear. This dimer consists of two centrosymmetrically related pseudo-five coordinate Cu(II) atoms 3.242(2) A apart and bridged by two dideprotonated salicylate ligands. The X-ray crystal structure of [bis(1,10-phenanthroline)(salicylato)copper(II)][salicylate] monohydrate, 2, ([Cu(II)(phen)(2)(Hsal)](+)[Hsal](-)[H(2)O]), shows it to be mononuclear. This complex cation exhibits a highly irregular distorted square pyramidal geometry about the Cu(II) atom, (4+1+1*). Each salicylate is singly deprotonated and one of them is ligand bonded in an asymmetric chelating mode. EPR results for 2 indicate that in concentrated DMF solution phen remains bonded to copper but salicylate is likely monodentate in contrast to the situation for 1. However, in dilute DMF solution, both 1 and 2 form the same species, which accounts for the similarity in anti-convulsant activity of the two compounds. Both 1 and 2 were found to be effective in preventing MES-induced seizures and ineffective in preventing Metrazol-induced seizures. Rotorod toxicity, consistent with central nervous system depression, paralleled the observed anti-convulsant activity. It is suggested that the observed anti-convulsant activity is consistent with central nervous system depression as a physiological mechanism in overcoming MES-induced seizures due to MES-induced brain inflammatory disease.

Animals↗

PubMed1975

Generality of the kindling phenomenon: some clinical implications.

The purpose of the present investigations was to explore the generality of the kindling phenomenon and its applicability to clinical situations. Whether local brain stimulation, electroconvulsive shock (ECS), or metrazol the consequence of periodic administration of convulsive agents was found to be the same; in each case repeated application of the agent resulted in the gradual development and intensification of convulsive symptoms (kindling). Moreover, in each case the resulting intensification was not specific to the agent being used and seemed to increase the responsiveness to convulsive agents in general. In the present studies this interaction was seen in the form of an intensified alcohol withdrawal syndrome observed 18 days after cessation of a series of metrazol injections, amygdaloid stimulations, of ECS. Thus, it appears that one of the hazards of the convulsive therapies is that they may induce enduring changes in brain function which leave the patient in a state of increased susceptibility to a variety of potentially convulsive agents.

Alcoholism↗

PubMed1997

Aroyl(aminoacyl)pyrroles, a new class of anticonvulsant agents.

2-Aroyl-4-(omega-aminoacyl)- (4) and 4-aroyl-2-(omega-aminoacyl)pyrroles (9) represent a new, structurally novel class of anticonvulsant agents. Compounds of type 4 were prepared by Friedel-Crafts acylation of a 2-aroylpyrrole with an omega-chloroacyl chloride followed by displacement of the chloro group by a primary or secondary amine. Compounds of type 9 were prepared by Friedel-Crafts aroylation of a 2-(omega-chloroacyl)pyrrole followed by displacement by an amine. These compounds were active in the mouse and rat maximal electroshock tests but not in the mouse metrazole test. The lead compound, RWJ-37868, 2-(4-chlorobenzoyl)-4-(1-piperidinyl-acetyl)-1,3,5-trimethylpyrrole++ + (4d), showed potency and therapeutic index comparable to those of phenytoin and carbamazepine and greater than those of sodium valproate. This compound blocked bicuculline induced seizures, did not elevate seizure threshold following iv infusion of metrazole, and blocked influx of Ca2+ ions into cerebellar granule cells induced by K+ or veratridine.

Anesthesia↗

PubMed1996

MKP-3, a novel cytosolic protein-tyrosine phosphatase that exemplifies a new class of mitogen-activated protein kinase phosphatase.

MKP-1 (also known as CL100, 3CH134, Erp, and hVH-1) exemplifies a class of dual-specificity phosphatase able to reverse the activation of mitogen-activated protein (MAP) kinase family members by dephosphorylating critical tyrosine and threonine residues. We now report the cloning of MKP-3, a novel protein phosphatase that also suppresses MAP kinase activation state. The deduced amino acid sequence of MKP-3 is 36% identical to MKP-1 and contains the characteristic extended active-site sequence motif VXVHCXXGXSRSXTXXXAYLM (where X is any amino acid) as well as two N-terminal CH2 domains displaying homology to the cell cycle regulator Cdc25 phosphatase. When expressed in COS-7 cells, MKP-3 blocks both the phosphorylation and enzymatic activation of ERK2 by mitogens. Northern analysis reveals a single mRNA species of 2.7 kilobases with an expression pattern distinct from other dual-specificity phosphatases. MKP-3 is expressed in lung, heart, brain, and kidney, but not significantly in skeletal muscle or testis. In situ hybridization studies of MKP-3 in brain reveal enrichment within the CA1, CA3, and CA4 layers of the hippocampus. Metrazole-stimulated seizure activity triggers rapid (<1 h) but transient up-regulation of MKP-3 mRNA in the cortex, piriform cortex, and some amygdala nuclei. Metrazole stimulated similar regional up-regulation of MKP-1, although this was additionally induced within the thalamus. MKP-3 mRNA also undergoes powerful induction in PC12 cells after 3 h of nerve growth factor treatment. This response appears specific insofar as epidermal growth factor and dibutyryl cyclic AMP fail to induce significant MKP-3 expression. Subcellular localization of epitope-tagged MKP-3 in sympathetic neurons reveals expression in the cytosol with exclusion from the nucleus. Together, these observations indicate that MKP-3 is a novel dual-specificity phosphatase that displays a distinct tissue distribution, subcellular localization, and regulated expression, suggesting a unique function in controlling MAP kinase family members. Identification of a second partial cDNA clone (MKP-X) encoding the C-terminal 280 amino acids of an additional phosphatase that is 76% identical to MKP-3 suggests the existence of a distinct structurally homologous subfamily of MAP kinase phosphatases.

Aging↗