Enabling dual cellular destinations of polymeric nanoparticles for treatment following partial injury to the central nervous system.

Following neurotrauma, oxidative stress is spread via the astrocytic syncytium and is associated with increased aquaporin 4 (AQP4), inflammatory cell infiltration, loss of neurons and glia and functional deficits. Herein we evaluate multimodal polymeric nanoparticles functionalized with an antibody to an extracellular epitope of AQP4, for targeted delivery of an anti-oxidant as a therapeutic strategy following partial optic nerve transection. Using fluorescence microscopy, spectrophotometry, correlative nanoscale secondary ion mass spectrometry (NanoSIMS) and transmission electron microscopy, in vitro and in vivo, we demonstrate that functionalized nanoparticles are coated with serum proteins such as albumin and enter both macrophages and astrocytes when administered to the site of a partial optic nerve transection in rat. Antibody functionalized nanoparticles synthesized to deliver the antioxidant resveratrol are effective in reducing oxidative damage to DNA, AQP4 immunoreactivity and preserving visual function. Non-functionalized nanoparticles evade macrophages more effectively and are found more diffusely, including in astrocytes, however they do not preserve the optic nerve from oxidative damage or functional loss following injury. Our study highlights the need to comprehensively investigate nanoparticle location, interactions and effects, both in vitro and in vivo, in order to fully understand functional outcomes.

The case for the development of novel analgesic agents targeting both fatty acid amide hydrolase and either cyclooxygenase or TRPV1.

Although the dominant approach to drug development is the design of compounds selective for a given target, compounds targeting more than one biological process may have superior efficacy, or alternatively a better safety profile than standard selective compounds. Here, this possibility has been explored with respect to the endocannabinoid system and pain. Compounds inhibiting the enzyme fatty acid amide hydrolase (FAAH), by increasing local endocannabinoid tone, produce potentially useful effects in models of inflammatory and possibly neuropathic pain. Local increases in levels of the endocannabinoid anandamide potentiate the actions of cyclooxygenase inhibitors, raising the possibility that compounds inhibiting both FAAH and cyclooxygenase can be as effective as non-steroidal anti-inflammatory drugs but with a reduced cyclooxygenase inhibitory 'load'. An ibuprofen analogue active in models of visceral pain and with FAAH and cyclooxygenase inhibitory properties has been identified. Another approach, built in to the experimental analgesic compound N-arachidonoylserotonin, is the combination of FAAH inhibitory and transient receptor potential vanilloid type 1 antagonist properties. Although finding the right balance of actions upon the two targets is a key to success, it is hoped that dual-action compounds of the types illustrated in this review will prove to be useful analgesic drugs.

Protective effect of quercetin against ICV colchicine-induced cognitive dysfunctions and oxidative damage in rats.

Intracerebroventricular (i.c.v.) administration of colchicine, a microtubule-disrupting agent, causes cognitive dysfunction and oxidative stress. The present study was designed to investigate the protective effects of quercetin against colchicine-induced memory impairment and oxidative damage in rats. An i.c.v. cannula was implanted in the lateral ventricle of male Wistar rats. Colchicine was administered at dose of 15 microg/rat. Morris water maze and plus-maze performance tests were used to assess memory tasks. Various biochemical parameters such as lipid peroxidation, reduced glutathione, nitrite level, acetylcholinesterase and proteins were also assessed. Central administration of colchicine (15 microg/rat) showed poor retention of memory. Chronic treatment with quercetin (20 and 40 mg/kg, p.o.) twice daily for a period of 25 days beginning 4 days prior to colchicine injection significantly improved the colchicine-induced cognitive impairment. Biochemical analysis revealed that i.c.v. colchicine injection significantly increased lipid peroxidation, nitrite and depleted reduced glutathione activity in the brains of rats. Chronic administration of quercetin significantly attenuated elevated lipid peroxidation and restored the depleted reduced glutathione, acetylcholinesterase activity and nitrite activity. The results of the present study clearly indicated that quercetin has a neuroprotective effect against colchicine-induced cognitive dysfunctions and oxidative damage. This article was published online on 3 November 2008. An error was subsequently identified. This notice is included in the online and print version to indicate that both have been corrected.

Effect of curcumin on intracerebroventricular colchicine-induced cognitive impairment and oxidative stress in rats.

This study was designed to investigate the protective effects of curcumin against colchicine-induced cognitive impairment and oxidative stress in rats. Male Wistar rats (weighing 150-200 g) received colchicine intracerebroventricularly (15 microg per rat), and cognitive dysfunctions were evaluated by the Morris water maze and the plus maze performance task and supported by biochemical tests. Central administration of colchicine caused memory deficit in both the Morris water maze and the elevated plus maze task paradigm tasks. Chronic treatment with curcumin (5-50 mg/kg, p.o.) twice daily for a period of 25 days beginning 4 days prior to colchicine injection significantly improved the colchicine-induced cognitive impairment. Biochemically, chronic administration of curcumin significantly reduced the elevated lipid peroxidation, restored the decreased reduced glutathione level and acetylcholinesterase activity, and attenuated the raised colchicine-induced elevated nitrite levels. The results of the present study indicate that curcumin has a protective role against colchicine-induced cognitive impairment and associated oxidative stress.

Cyclooxygenase inhibition attenuates 3-nitropropionic acid-induced neurotoxicity in rats: possible antioxidant mechanisms.

Systemic administration of 3-nitropropionic acid (3-NP), a complex II inhibitor of the electron transport chain, causes motor and cognitive deficits that are associated with excitotoxicity and excessive free radical generation. Recently, cyclooxygenase (COX) inhibitors have been implicated as a neuroprotectant in the treatment of various neurological disorders. The present study was designed to investigate the effects of COX inhibitors in 3-NP-induced cognitive impairment and oxidative stress in rats. Intraperitoneal administration of 3-NP (20 mg/kg for 4 days) showed motor abnormalities and cognitive impairment in rats. Chronic treatment with naproxen (10 and 20 mg/kg) and valdecoxib (5 and 10 mg/kg) once daily for a period of 8 days beginning 4 days prior to 3-NP administration significantly improved 3-NP-induced motor and cognitive impairment in rats. Biochemical analysis revealed that systemic 3-NP administration significantly increased lipid peroxidation and nitrite levels, depleted reduced glutathione levels and reduced succinate dehydrogenase (SDH) activity in the brains of rats, whereas administration of naproxen, a nonselective COX inhibitor (10 and 20 mg/kg p.o.) and valdecoxib, a selective COX-2 inhibitor (5 and 10 mg/kg p.o.) significantly attenuated 3-NP-induced oxidative stress. Cyclooxygenase inhibitors also significantly restored the decreased SDH activity. The results of the present study clearly indicate that naproxen and valdecoxib showed protection against 3-NP-induced motor and cognitive impairment by decreasing oxidative stress.

Possible neuroprotective mechanisms of curcumin in attenuating 3-nitropropionic acid-induced neurotoxicity.

3-Nitropropionic acid (3-NP) is a well known fungic toxin causing neurotoxicity. Systemic administration of 3-NP causes motor and cognitive deficits that are associated with excessive free radical generation. Recently, curcumin has been implicated as a neuroprotectant in the treatment of various neurological disorders. The present study was designed to investigate the effects of curcumin in 3-NP-induced cognitive impairment and oxidative stress in rats. Curcumin, a potent antioxidant of dietary polyphenol, containing a standardized extract of Curcuma longa root (Zingiberaceae), has been reported to possess free radical scavenging, iron chelating and antiinflammatory activities. Intraperitoneal administration of 3-NP (20 mg/kg for 4 days) showed loss in body weight, declined motor function, poor retention of memory and changes in oxidative stress (lipid peroxidation, reduced glutathione and nitrite level) parameters in brain. Chronic treatment with curcumin (10, 20 and 50 mg/kg, p.o.) once daily for a period of 8 days beginning 4 days prior to 3-NP administration dose-dependently improved the 3-NP-induced motor and cognitive impairment. Biochemical analysis revealed that curcumin administration significantly attenuated 3-NP-induced oxidative stress (lipid peroxidation estimation, reduced glutathione and nitrite activity) in the brains of rats. It also significantly restored the decreased succinate dehydrogenase activity. The results of the present study clearly indicate that curcumin by its antioxidant activity showed neuroprotection against 3-NP-induced behavioral and biochemical alteration.

Neuroprotective effects of resveratrol against intracerebroventricular colchicine-induced cognitive impairment and oxidative stress in rats.

Alzheimer's disease is a complex and multifactorial neurodegenerative disease. Central administration of colchicine, a microtubule-disrupting agent, causes loss of cholinergic neurons and cognitive dysfunction that is associated with excessive free radical generation. The present study was aimed at evaluating the effects of trans-resveratrol in the prevention of colchicine-induced cognitive impairment and oxidative stress in rats. Intracerebroventricular administration of colchicine (15 microg/5 microl) induced impaired cognitive functions in both the Morris water maze task and the elevated plus-maze task. Chronic treatment with resveratrol (10 and 20 mg/kg, p.o.) for a period of 25 days, beginning 4 days prior to colchicine injection, significantly improved the colchicine-induced cognitive impairment. Intracerebroventricular colchicine injection resulted in free radical generation characterized by alterations in oxidative stress markers with a significant increase in malondialdehyde (MDA) and nitrite levels and depletion of reduced glutathione (GSH) activity in the rat brains. It also showed a significant decrease in acetylcholinesterase activity. Besides improving cognitive dysfunction, chronic administration of resveratrol significantly reduced the elevated MDA and nitrite levels and restored the depleted GSH and acetylcholinesterase activity. Results of the present study indicated that trans-resveratrol has a neuroprotective role against colchicine-induced cognitive impairment and associated oxidative stress.

Involvement of peripheral prostaglandins in formalin-induced nociceptive behaviours in the orofacial area of rats.

Prostaglandins (PGs) are known to be involved in the pathogenesis of inflammation and pain. However, their role in orofacial pain is not clearly understood. The present study was undertaken to determine the effect of systemic and locally administered nonsteroidal anti-inflammatory drugs (NSAIDs) on the role of PGs in orofacial pain induced by formalin in rats. The subcutaneous injection of formalin into the rat upper lip generated behavioural responses that lasted for several minutes. The orofacial responses due to formalin were seen in two distinct phases, the early response (0-3 min) and the continuous prolonged response (9-45 min). Systemic administration of ketorolac or diclofenac (10 and 30 mg/kg, i.p.) significantly attenuated formalin-induced nociceptive behaviour in the phase-2, but not in the phase-1 of the formalin test. Similarly, subcutaneous (local) administration of ketorolac or diclofenac in the orofacial area (100 and 300 microg/lip) markedly decreased the phase-2 nociceptive response due to formalin. However, both the drugs had no effect on the phase-1 response of the formalin test. These results suggest that PGs, particularly peripheral PGs are involved in nociceptive behaviour following formalin injection in the orofacial area.

Protective effect of quercetin on alcohol abstinence-induced anxiety and convulsions.

Chronic administration of ethanol (2 g/kg, p.o.) on days 1-6 and its withdrawal produced an anxiogenic reaction in mice as assessed in the mirrored-chamber test. Daily administration of quercetin (25 or 50 mg/kg, p.o.) prior to ethanol for 6 days prevented withdrawal-induced anxiety in mice. However, acute administration of a single dose of quercetin (50 mg/kg) to animals withdrawn from ethanol, i.e., on day 7, did not prevent withdrawal-induced anxiety. Ethanol withdrawal also induced a significant increase in the locomotor activity of mice indicating an anxiogenic response. Daily administration of quercetin (25 or 50 mg/kg, p.o.) prior to ethanol for 6 days prevented withdrawal-induced increased locomotor activity. Ethanol withdrawal also sensitized the convulsogenic reaction to pentylenetetrazole (PTZ). A non-convulsive dose (40-60 mg/kg) of PTZ produced full-blown convulsions and increased mortality in ethanol-withdrawn mice. Both acute and chronic administration of quercetin (25 or 50 mg/kg, p.o.) produced a significant protection against ethanol withdrawal-induced reduction in PTZ threshold in mice. The result suggests the protective effect of this safe drug, quercetin, in the management of ethanol withdrawal reactions.

Protective effect of bupropion on morphine tolerance and dependence in mice.

Possible reversal of morphine-induced tolerance and dependence by bupropion was studied in mice. A 10-day repeated injection regimen was followed to induce morphine tolerance and dependence. Bupropion (2 and 5 mg/kg) per se, when chronically administered for 9 days, failed to produce any significant change in tail-flick latency compared with the control mice. Chronic administration of bupropion (2 or 5 mg/kg) during the induction phase (days 1-9) delayed the development of tolerance to the antinociceptive action of morphine and also reversed naloxone- (2 mg/kg) precipitated withdrawal jumps. On the other hand, acute administration of bupropion (2 or 5 mg/kg) on day 10, i.e., during the expression phase of morphine dependence, reduced the incidence of naloxone-precipitated withdrawal jumps without affecting tolerance to the analgesic effect. In conclusion, results of the present study suggest the potential use of bupropion in tolerance and dependence.

Quercetin, a bioflavonoid, reverses haloperidol-induced catalepsy.

Neuroleptics are extensively used in the treatment of schizophrenia and other affective disorders. Unfortunately their use is often associated with distressing side effects involving the extrapyramidal tract, such as Parkinsonism and tardive dyskinesia. Neuroleptic-induced catalepsy has long been used as a model for extrapyramidal side effects such as Parkinsonian-like bradykinesia associated with antipsychotic use in humans. In the present study, haloperidol (2 mg/kg i.p.) was administered to mice to induce catalepsy and cataleptic response was measured for the next 4 h at 1 h intervals. Haloperidol treatment in mice induced a strong cataleptic state within 1 h of injection, reaching a maximal plateau after 2 h and lasting for 4 h. Vehicle-treated animals did not display catalepsy as they remained less than 5 sec on the bar at each time point. Pretreatment with quercetin dose-dependently (25-100 mg/kg p.o.) reduced the catalepsy score in haloperidol-treated animals. A dose response study of quercetin showed a characteristic U-shaped response curve, with maximum suppression observed at a dose of 100 mg/kg. On increasing the dose of quercetin to 300 mg/kg, no statistically significant difference in catalepsy score was observed compared with the haloperidol-treated group. In conclusion, the findings of the present study strongly suggest that quercetin can be screened as a potential drug candidate or as an adjuvant for the treatment of neuroleptic-induced extrapyramidal side effects.

Possible involvement of prostaglandins in haloperidol-induced orofacial dyskinesia in rats.

Dopaminergic abnormality is one of the pathological mechanisms involved in the pathophysiology of tardive dyskinesia, a late complication of neuroleptic treatment. Prostaglandins modulate the dopamine release in the striatum, the principle area involved in the pathophysiology of tardive dyskinesia. Rats were chronically treated with haloperidol (HPD) (1.5 mg/kg) for a period of 21 days, to induce orofacial dyskinesia. Behavioural assessment of orofacial dyskinesia was done 24 h after the last dose of haloperidol. Catalepsy was induced in rats by acute treatment with haloperidol (1 mg/kg), and catalepsy was scored for the next 4 h. Chronic haloperidol treatment induced profound vacuous chewing movements in rats. Indomethacin, a nonselective cyclooxygenase inhibitor dose-dependently (5-20 mg/kg) suppressed the vacuous chewing movements count in haloperidol-treated animals. In conclusion, the results of the present study infer that prostaglandins might play a significant role in the haloperidol-induced vacuous chewing movements, and prostaglandin synthesis inhibitors can serve as novel drug candidates for the treatment of tardive dyskinesia.

Excitatory mechanisms in neuroleptic-induced vacuous chewing movements (VCMs): possible involvement of calcium and nitric oxide.

Tardive dyskinesia (TD) is a serious motor side-effect of chronic neuroleptic therapy. Chronic treatment with neuroleptics leads to the development of oral abnormal movements in rats known as vacuous chewing movements (VCMs). Vacuous chewing movements in rats have been widely accepted as an animal model of tardive dyskinesia. Chronic blockade of D2 inhibitory dopamine (DA) receptors localized on glutamatergic terminals in the striatum leads to the persistent enhanced release of glutamate that kills the striatal output neurons. The object of the present study was to explore the role of glutamatergic modulation on the neuroleptic-induced VCMs. Rats were chronically (for 21 days) treated with haloperidol (1.5 mg/kg, i.p.) to produce VCMs. The neuroleptic-induced VCMs viz., vertical jaw movements, tongue protrusions and bursts of jaw tremors, were counted during a 5 min observation period. Dizocilpine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, dose dependently (0.02 and 0.05 mg/kg) reduced haloperidol-induced VCMs. Felodipine (5 and 10 mg/kg), an L-type calcium-channel blocker, also significantly reduced the VCM count. N-omega-nitro-L-arginine methyl ester (L-NAME) (25 and 50 mg/kg), a nitric oxide synthase inhibitor, also reduced the VCM count in an L-arginine-sensitive manner. In conclusion, the findings of the present study indicated NMDA receptor involvement in haloperidol-induced VCMs, and also suggested the possible involvement of calcium and nitric oxide in haloperidol-induced VCMs.

Reversal of reserpine-induced vacuous chewing movements in rats by melatonin: involvement of peripheral benzodiazepine receptors.

Several reports have indicated that melatonin modulates striatal dopaminergic functions via its interaction with central and peripheral benzodiazepine (BZ) receptors. Clinical reports and animal studies speculated on the possible involvement of melatonin in the pathophysiology of tardive dyskinesia (TD). In view of this, the present experiment was performed to study the possible effect of melatonin in modulation of reserpine-induced dyskinesia. Melatonin (1-10 mg/kg) dose dependently suppressed the severity of vacuous chewing movements (VCMs) in rats. Prior administration of the putative melatonin receptor antagonists luzindole (2.5 and 5 mg/kg) or prazosin (2.5 and 5 mg/kg) failed to antagonize melatonin (2.5 mg/kg) reversal of reserpine-induced VCMs. However, the peripheral BZ receptor antagonist PK11195 (0.5 and 1 mg/kg) but not flumazenil (1 and 2 mg/kg), dose dependently antagonized melatonin's reversal of reserpine-induced VCMs. Taken together the present results demonstrate that melatonin reverses reserpine-induced VCMs and that this could be due to enhancement of GABAergic activity via peripheral BZ receptors.

Animal models of tardive dyskinesia--a review.

Tardive dyskinesia is a serious motor side effect of long term neuroleptic therapy, with an unknown pathophysiological basis. The leading hypothesis of the pathophysiology of tardive dyskinesia includes dopamine receptor supersensitivity, GABAergic hypofunction, excitotoxicity and oxidative stress. Many preclinical models have been developed to identify the underlying pathological processes of tardive dyskinesia, but none has yet produced a parsimonious results. A wide range of animal models, viz. Homologous, analogous and correlational models have been developed to explore the pathophysiology of tardive dyskinesia. Vacuous chewing movements in rodents induced by chronic neuroleptic treatment is the most frequently employed model. As the existing models suffer from several phenomenological and methodological problems, development of new models, highly predictive of pathological basis of tardive dyskinesia can accelerate tardive dyskinesia research for the better understanding of the pathophysiological processes underlying the syndrome and for the discovery of new therapeutic targets for the treatment of tardive dyskinesia.

Reversal of neuroleptic-induced orofacial dyskinesia by 5-HT3 receptor antagonists.

Tardive dyskinesia, a syndrome of abnormal, involuntary hyperkinetic movements that occurs during long-term neuroleptic therapy is a major limitation of chronic neuroleptic therapy. The pathophysiology of tardive dyskinesia is still an enigma. The objective of the present study was to elucidate the role of 5-HT3 receptor involvement in neuroleptic-induced vacuous chewing movements in rats. Rats chronically (for 21 days) treated with haloperidol (1.5 mg/kg, i.p.) significantly developed vacuous chewing movements, as compared to vehicle-treated controls. Both ondansetron and tropisetron dose-dependently (0.25, 0.5 and 1.0 mg/kg, i.p.) reversed the haloperidol-induced vacuous chewing movements. Serotonin acting through 5-HT3 receptors might play a significant role in the pathophysiology of tardive dyskinesia, and 5-HT3 receptor ligands can be exploited as novel therapeutic agents for the treatment of tardive dyskinesia.

Tardive dyskinesia: An update.

Tardive dyskinesia (TD) is a serious motor side effect of chronic neuroleptic therapy. TD is a complex hyperkinetic syndrome consisting of choreiform, athetoid or rhythmic abnormal involuntary movements. The face, mouth and tongue are most frequently involved (orofacial type), but a variety of less frequent motor abnormalities of the upper and lower limbs and of the trunk may also occur. TD usually has a delayed onset and the intensity of the syndrome may fluctuate over time. The most serious aspect of TD is that it may persist for months or years after drug withdrawal and in some patients is irreversible. In spite of the prevalence and known etiology that chronic neuroleptic treatment causes TD, relatively little is known about the primary pathological mechanism underlying the condition. Abnormalities in various neurotransmitter systems have been implicated in the pathophysiology of TD, including the dopaminergic, GABAergic, serotonergic and noradrenergic systems. Recently, excitotoxicity of the glutamatergic system and oxidative stress have received much attention. Three general types of animal models have contributed to our knowledge of TD and can be described as homologous, analogous and correlational models. There are no empirically validated guidelines to follow when choosing a suppressive agent. In general, therapeutic trials have attempted to manipulate the dopaminergic, GABAergic, serotonergic and noradrenergic systems, in part due to theories on the pathophysiology of TD. None of these medications has proven successful in the majority of patients. Much more research is needed in order to increase our understanding of TD and to develop better therapeutics for its treatment. (c) 2001 Prous Science. All rights reserved.

Effect of 5-HT1A and 5-HT2A/2C receptor modulation on neuroleptic-induced vacuous chewing movements.

Tardive dyskinesia is a serious motor side effect of chronic neuroleptic therapy. Chronic treatment or rats with neuroleptics leads to the development of abnormal oral movements called vacuous chewing movements. Vacuous chewing movements in rats are widely accepted as an animal model of tardive dyskinesia. Atypical antipsychotics such as clozapine and rispiridone are associated with a lower incidence of extrapyramidal side effects and tardive dyskinesia. The present study was aimed to explore the role of 5-HT1A, 5-HT2A/2C receptors in the expression of neuroleptic-induced orofacial dyskinesia. In the present study rats were chronically (for 21 days) treated with haloperidol (1.5 mg/kg, i.p.) to elicit vacuous chewing movements. The neuroleptic-induced vacuous chewing movements, viz., vertical jaw movements, tongue protrusions and bursts of jaw tremors, were counted during a 5-min observation period. Acute treatment with 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, dose-dependently (0.05, 0.1 and 0.2 mg/kg, i.p.) reduced the haloperidol-induced vacuous chewing movements and headshakes. Both acute and chronic administration of seganserin, ketanserin and ritanserin, 5-HT2A/2C receptor antagonists, also reduced haloperidol-induced vacuous chewing movements in a dose-dependent (0.05, 0.1 and 0.2 mg/kg, i.p.) manner. In acute studies a higher dose of ritanserin (1 mg/kg) but not ketanserin (1 mg/kg) increased vacuous chewing movements, whereas a higher dose of seganserin (1 mg/kg) did not have any effect on vacuous chewing movements. All the drugs reduced haloperidol-induced headshakes in a dose-dependent fashion. These findings indicate that the serotonergic system, and particularly 5-HT1A and 5-HT2A/2C receptors, may be involved in haloperidol-induced orofacial dyskinesia, and that 5-HT receptors may provide novel targets for the development of drugs that can be used to reverse or prevent the extrapyramidal side effects associated with long-term antipsychotic treatment.

Differential role of dopamine D1 and D2 receptors in isoniazid-induced vacuous chewing movements.

Tardive dyskinesia (TD) is a syndrome of potentially irreversible and involuntary hyperkinetic disorders that occurs during chronic neuroleptic therapy and is a major limitation of such therapy. Vacuous chewing movements (VCMs) in rats have been widely accepted as an animal model of tardive dyskinesia. In the present study isoniazid (1, 2 and 5 microM i.c.v.) dose-dependently produced VCMs in rats. The response produced by a 10-microM dose was lower than that of earlier doses but was statistically significant when compared to a saline-treated group. Diazepam (1 and 4 mg/kg i.p.) and progabide (50 and 100 mg/kg i.p.) dose-dependently reversed the isoniazid-induced VCMs. Haloperidol (0.5 and 1 mg/kg i.p.) and SCH-23390 (0.25 and 0.5 mg/kg i.p.) reversed the isoniazid-induced VCMs in a dose-dependent manner. Sulpiride (25 and 50 mg/kg i.p.), a dopamine D2 receptor antagonist, had no effect on isoniazid-induced VCMs. SKF-38393 (10 and 15 mg/kg i.p.) dose-dependently augmented the isoniazid-induced VCMs. Quinpirole 0.02 mg/kg i.p. had no effect on isoniazid-induced VCMs but a higher quinpirole dose (0.05 mg/kg) significantly reduced isoniazid-induced VCMs. Isoniazid (2 microM i.c.v.) produced stereotypy (grooming and rearing) in rats. Haloperidol (0.5 and 1 mg/kg i.p.), SCH-23390 (0.25 and 0.5 mg/kg i.p.) and sulpiride (25 and 50 mg/kg i.p.) decreased the severity of isoniazid-induced stereotypy. SKF-38393 (10 and 15 mg/kg i.p.) dose-dependently augmented the isoniazid-induced grooming behavior more prominently as compared to quinpirole (0.02 and 0.05 mg/kg i.p.); on the other hand quinpirole potentiated isoniazid-induced rearing behavior. In conclusion, the results of the present study demonstrated the differential involvement of dopamine D1 and D2 receptors in isoniazid-induced VCMs.

Calcium-calmodulin mediates bradykinin-induced MAPK phosphorylation and c-fos induction in vascular cells.

The vasoactive peptide bradykinin (BK) has been implicated in the pathophysiology of a number of vascular wall abnormalities, but the cellular mechanisms by which BK generates second messengers that alter vascular function are as yet undefined. Exposure of vascular smooth muscle cells (VSMC) to BK (10(-7) M) produced a rapid and transient rise in intracellular calcium, which preceded an increase in tyrosine phosphorylation of mitogen-activated protein kinase (MAPK). MAPK activation by BK was observed as early as 1 min, peaked at 5 min, and returned to baseline by 20 min. Treatment of cells with the intracellular calcium chelator EGTA-acetoxymethyl ester inhibited BK-stimulated MAPK activation, suggesting that intracellular calcium mobilization contributes to the activation of MAPK. The calmodulin inhibitor W-7 also markedly inhibited BK-induced MAPK phosphorylation in the cytoplasm as well as in the nucleus. Moreover, the BK-induced increase in c-fos mRNA levels was significantly inhibited by the calmodulin inhibitor, indicating that calmodulin is required for BK signaling leading to c-fos induction. These results implicate the calcium-calmodulin pathway in the mechanisms for regulating MAPK activity and the resultant c-fos expression induced by BK in VSMC.