Haloperidol-induced Catalepsy In Mice Research Articles

The mGlu5 Receptor Protomer-Mediated Dopamine D2 Receptor Trans-Inhibition Is Dependent on the Adenosine A2A Receptor Protomer: Implications for Parkinson’s Disease

The adenosine A2A receptor (A2AR), dopamine D2 receptor (D2R) and metabotropic glutamate receptor type 5 (mGluR5) form A2AR-D2R-mGluR5 heteroreceptor complexes in living cells and in rat striatal neurons. In the current study, we present experimental data supporting the view that the A2AR protomer plays a major role in the inhibitory modulation of the density and the allosteric receptor-receptor interaction within the D2R-mGluR5 heteromeric component of the A2AR-D2R-mGluR5 complex in vitro and in vivo. The A2AR and mGluR5 protomers interact and modulate D2R protomer recognition and signalling upon forming a trimeric complex from these receptors. Expression of A2AR in HEK293T cells co-expressing D2R and mGluR5 resulted in a significant and marked increase in the formation of the D2R-mGluR5 heteromeric component in both bioluminescence resonance energy transfer and proximity ligation assays. A highly significant increase of the the high-affinity component of D2R (D2RKi High) values was found upon cotreatment with the mGluR5 and A2AR agonists in the cells expressing A2AR, D2R and mGluR5 with a significant effect observed also with the mGluR5 agonist alone compared to cells expressing only D2R and mGluR5. In cells co-expressing A2AR, D2R and mGluR5, stimulation of the cells with an mGluR5 agonist like or D2R antagonist fully counteracted the D2R agonist-induced inhibition of the cAMP levels which was not true in cells only expressing mGluR5 and D2R. In agreement, the mGluR5-negative allosteric modulator raseglurant significantly reduced the haloperidol-induced catalepsy in mice, and in A2AR knockout mice, the haloperidol action had almost disappeared, supporting a functional role for mGluR5 and A2AR in enhancing D2R blockade resulting in catalepsy. The results represent a relevant example of integrative activity within higher-order heteroreceptor complexes.

IN VITRO ANTIOXIDANT AND ANTI-DOPAMINERGIC ACTIVITY OF ALKALOID-RICH FRACTION ISOLATED FRO MLEAVES OF MURRAYA KOENIGII

Anti-dopaminergic or dopamine antagonists are preferably used as anti-psychotics, in schizophrenia, bipolar disorders and stimulant psychosis. They are also effective in many other gastrointestinal disorders including nausea and vomiting. Many herbal drugs like digoxin, quinine, morphine, are known for their therapeutic importance. The objective of this study was to use animal models to investigate the impact of Murraya koenigii L. leaves (MK) as an anti-dopaminergic.Pet ether extract of MK (PEMK) and alkaloids isolated from PEMK (AFMK) has shown potent antioxidant activity when tested against invitro antioxidant methods like free radical scavenging by DPPH method, total antioxidant activity by thiocyanate method and H2O2scavenging activity. Significant decreasein the dopaminergic activity was observed in validated animal models like haloperidol-induced catalepsy in mice, apomorphine-induced stereotypic behavior, foot shock-induced aggression and phenobarbitone-induced sleeping behavior. This may be attributed to the presence of carbazole alkaloids having antioxidant potential.

Naringin exhibited Anti-Parkinsonian like effect against haloperidol-induced catalepsy in mice

Parkinsonism is a neurological disorder associated with a group of various motor-related symptoms such as tremor, rigidity, hypokinesia, defective gait, etc. It is caused by the degeneration of dopaminergic neurons in the nigrostriatal tract. Accompanying various side effects with existing treatment options such as levodopa, selegiline, entacapone limits its usage in weak and aged patients. Considering the adverse reaction with the usage of present medications, there is a need to explore the beneficial effects of products from complementary medicine such as flavonoids. Naringin is one such flavonoid which possesses antioxidant effects along with neuroprotection to the nigrostriatal dopaminergic projecting neurons. Taking this as a clue this study was designed to explore the antiparkinsonian action of naringin in haloperidol-induced catalepsy in Swiss albino mice. In this study, animals were divided into five groups and catalepsy was induced in the mouse by intraperitoneal injection of haloperidol (1.5mg/kg). All the treatments with vehicle or naringin were performed 30 min prior to haloperidol injection. Catalepsy score was used as an indicator of behavior mechanism because of its similarity to PD symptoms, which was determined. Naringin treatment showed a reduction in haloperidolinduced cataleptic scores in both bar test and block test after 1 hour of treatment (except 100mg/kg in bar test) as compared with the normal control group. These effects could be attributed due to either dopamine agonist activity or due to its effect on raising dopamine levels in the nigrostriatal tract. However, the mechanisms behind the neuroprotective effect of naringin are not fully defined. Thus, we can conclude that naringin can protect against drug-induced Parkinson’s disease.

Effect of methonolic extract of Vitex negundo on haloperidol induced catalepsy in albino mice

Background: Plants are being used in traditional medicine since history of mankind. The knowledge of these medicinal plants has accrued in the course of many centuries leading to medicinal systems in India such as Ayurveda, Unani and Siddha. Objective: In the present study, we evaluated the anticataleptic efficacy of Vitex negundo, a polyherbal formulation in haloperidol induced catalepsy in mice.Methods: Five groups (n=6) of male albino mice were used in the study. Catalepsy was induced by i.p. administration of haloperidol (1 mg/kg). The degree of catalepsy (cataleptic score) was measured as the time the animal maintained an imposed posture. We compared the anticataleptic efficacy of Vitex negundo (50, 100, 200 mg/kg) with standard received Pheniramine maleate 10 mg/kg, i.p.Results: In vehicle treated animals, haloperidol (1 mg/kg. i.p.) produced the maximum catalepsy at 180 min (46.78±3.78 min). Standard treated as Pheniramine maleate 10 mg/kg, i.p. shows maximum at 120 min. 19.24±1.32. Test herb, i.p. Methanolic extract of Vitex negundo (50, 100, 200 mg/kg, i.p.) significantly potentiated haloperidol induced catalepsy at each time interval, in a dose dependent manner. At dose 50, 100 and 200mg/kg, extract of Vitex negundo (Linn.) roots showed maximum cataleptic score 12.34±0.78, 14.43±0.43 and 15.43±0.67 min, respectively at 120 minutes in haloperidol treated animals.Conclusions: The present study indicates that the methanolic extract of Vitex negundo reduces haloperidol-induced catalepsy in mice.

Mitragyna speciosa Leaf Extract Exhibits Antipsychotic-Like Effect with the Potential to Alleviate Positive and Negative Symptoms of Psychosis in Mice.

In this study, we investigated the antipsychotic-like effect of methanolic extract of Mitragyna speciosa leaf (MMS) using in vivo and ex vivo studies. In vivo studies comprised of apomorphine-induced climbing behavior, haloperidol-induced catalepsy, and ketamine-induced social withdrawal tests in mice whereas the ex vivo study was conducted utilizing isolated rat vas deferens preparation. Acute oral administration of MMS (50–500 mg/kg) showed an inverted bell-shaped dose-response in apomorphine-induced cage climbing behavior in mice. The effective inhibitory doses of MMS (75 and 100 mg/kg, p.o.) obtained from the apomorphine study was further tested on haloperidol (subcataleptic dose; 0.1 mg/kg, i.p.)-induced catalepsy in the mouse bar test. MMS (75 and 100 mg/kg, p.o.) significantly potentiated the haloperidol-induced catalepsy in mice. Interestingly, MMS at the same effective doses (75 and 100 mg/kg, p.o.) significantly facilitated the social interaction in ketamine-induced social withdrawal mice. Furthermore, MMS inhibited the dopamine-induced contractile response dose-dependently in the isolated rat vas deferens preparations. In conclusion, this investigation provides first evidence that MMS exhibits antipsychotic-like activity with potential to alleviate positive as well as negative symptoms of psychosis in mice. This study also suggests the antidopaminergic activity of MMS that could be responsible for alleviating positive symptoms of psychosis.

Effect of Tribulus terrestris on Haloperidol-induced Catalepsy in Mice.

Haloperidol, an antipsychotic drug, leads to the development of a behavioural state called catalepsy, in which the animal is not able to correct an externally imposed posture. In the present study we have attempted to evaluate the anticataleptic effect of Tribulus terrestris on haloperidol-induced catalepsy in albino mice. Mice were allocated to four groups, each group containing six animals. Both, the test drug, Tribulus terrestris and the standard drug trihexyphenidyl were uniformly suspended in 1% gum acacia solution. Catalepsy was induced in mice with haloperidol (1.0 mg/kg, intraperitoneally). The first group received the vehicle (10 ml/kg, orally), the second group received trihexyphenidyl (10 mg/kg, orally) and the remaining two groups received Tribulus terrestris (100, 200 mg/kg, orally). The animals were assessed after single and repeated dose administration for ten days, 30 min prior to haloperidol, using standard bar test. The result of the present study demonstrates Tribulus terrestris has a protective effect against haloperidol-induced catalepsy, which is comparable to the standard drug used for the same purpose. Our study indicates Tribulus terrestris can be used to prevent haloperidol-induced extrapyramidal side effects.

Animal models of Parkinson׳s disease: Effects of two adenosine A2A receptor antagonists ST4206 and ST3932, metabolites of 2-n-Butyl-9-methyl-8-[1,2,3]triazol-2-yl-9H-purin-6-ylamine (ST1535)

Antagonism of the adenosine A2A receptor represents a promising strategy for non-dopaminergic treatment of Parkinson׳s disease (PD). Previously, the adenosine A2A receptor antagonist ST1535 was shown to possess potential beneficial effects in animal models of PD. Two metabolites of ST1535, namely ST3932 and ST4206, were tested in vitro to assess their affinity and activity on cloned human A2A adenosine receptors, and their metabolic profile. Additionally, ST3932 and ST4206 were investigated in vivo in animal models of PD following oral/intraperitoneal administration of 10, 20 and 40mg/kg using ST1535 as a reference compound. ST3932 and ST4206 displayed high affinity and antagonist behaviour for cloned human adenosine A2A receptors. The Ki values for ST1535, ST3932 and ST4206 were 8, 8 and 12nM, respectively, and their IC50 values on cyclic AMP were 427, 450 and 990nM, respectively. ST1535, ST3932 and ST4206 antagonized (orally) haloperidol-induced catalepsy in mice, potentiated (intraperitoneally) the number of contralateral rotations induced by l-3,4-dihydroxyphenylalanine (l-DOPA) (3mg/kg) plus benserazide (6mg/kg) in 6-Hydroxydopamine hydrobromide (6-OHDA)-lesioned rats, and increased mouse motor activity by oral route. Thus, ST3932 and ST4206, two ST1535 metabolites, show a pharmacological activity similar to ST1535, both in vitro and in vivo, and may be regarded as an interesting pharmacological alternative to ST1535.

Novel action of metformin in the prevention of haloperidol-induced catalepsy in mice: Potential in the treatment of Parkinson's disease?

Metformin is widely used to treat type II diabetes and other metabolic syndromes. In addition, it has been shown to increase neurogenesis, spatial memory formation and reduce the risk of Parkinson's disease. On this basis, the aim of the present study was the investigation of the protective potential of metformin in the haloperidol-induced catalepsy model of Parkinson's disease in mice. The effect of metformin (20 - 100mg/kg, p.o) on motor coordination was assessed using rotarod and forced swimming tests (FST), while the effect on memory function was evaluated using the Y-maze test. The neuroprotective activity was investigated in acute/chronic (21days) haloperidol-induced catalepsy in mice. On the 21st day, biochemical estimation of nitrosative and oxidative stress parameters was carried out. Metformin (50 or 100mg/kg, p.o.) did not affect motor coordination in rotarod test and FST but significantly reversed haloperidol-induced memory deficit (+35.50%) at 100mg/kg. Importantly, metformin significantly reduced the duration of catalepsy score during acute and chronic catalepsy tests as compared to trihexylphenidyl (reference standard). Intraperitoneal chronic injection of haloperidol (1mg/kg) significantly increased malondialdehyde and nitrite levels, while it significantly attenuated the activity of reduced glutathione, catalase and superoxide dismutase. Moreover, oral chronic administration of metformin significantly attenuated the haloperidol-induced increase of malondialdehyde and nitrite, as well as the deficit of glutathione and catalase. These findings suggest that metformin protects against haloperidol-induced catalepsy through inhibition of oxidative/nitrosative stress and has the potential for adjuvant action in the management of Parkinson's disease.

Synthesis of (E)-8-(3-Chlorostyryl)caffeine Analogues Leading to 9-Deazaxanthine Derivatives as Dual A2A Antagonists/MAO-B Inhibitors

A systematic modification of the caffeinyl core and substituents of the reference compound (E)-8-(3-chlorostyryl)caffeine led to the 9-deazaxanthine derivative (E)-6-(4-chlorostyryl)-1,3,5,-trimethyl-1H-pyrrolo[3,2-d]pyrimidine-2,4-(3H,5H)-dione (17f), which acts as a dual human A(2a) antagonist/MAO-B inhibitor (K(i)(A(2A)) = 260 nM; IC(50)(MAO-B) = 200 nM; IC(50)(MAO-A) = 10 μM) and dose dependently counteracts haloperidol-induced catalepsy in mice from 30 mg/kg by the oral route. The compound is the best balanced A(2A) antagonist/MAO-B inhibitor reported to date, and it could be considered as a new lead in the field of anti-Parkinson's agents. A number of analogues of 17f were synthesized and qualitative SARs are discussed. Two analogues of 17f, namely 18b and 19a, inhibit MAO-B with IC(50) of 68 and 48 nM, respectively, being 5-7-fold more potent than the prototypical MAO-B inhibitor deprenyl (IC(50) = 334 nM).

Structure-based design, synthesis, and molecular modeling studies of 1-(benzo[d]thiazol-2-yl)-3-(substituted aryl)urea derivatives as novel anti-Parkinsonian agents

1-(Benzo[d]thiazol-2-yl)-3-(substituted aryl)urea derivatives were designed and synthesized as our efforts to discover novel anti-Parkinsonian agents with improved pharmacological profile in haloperidol-induced catalepsy and oxidative stress in mice. All of the compounds were found to be active in alleviating haloperidol-induced catalepsy in mice. Furfuryl, 2- and/or 3-methoxy substituted phenyl derivatives emerged as potent agents. With exception of 2-chloro,5-trifluoromethyl-substituted analog, halogen-substituted derivatives exhibited moderate anti-Parkinsonian activity. Biochemical estimations of malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) from brain homogenate were carried out to highlight the neuroprotective properties associated with them. Molecular docking studies of these compounds with adenosine A2A receptor exhibited very good binding interactions and warrants further studies to confirm their binding with human A2A receptor for the design and development of potent antagonists. Parameters for Lipinski’s rule of 5 were calculated computationally because pharmacokinetic and metabolic behaviors in the body often are linked to the physical properties of a compound. None of the synthesized compounds violated Lipinski’s rule, making them suitable drug candidate for the treatment of Parkinson’s disease.

Ethanolic extract of Rubia peregrina L. (Rubiaceae) inhibits haloperidol-induced catalepsy and reserpine-induced orofacial dyskinesia

In the traditional Sardinian system of medicine, Rubia peregrina L. (Rubiaceae) is reported as an aphrodisiac herb. Since the aphrodisiacs may also have antioxidant and dopaminergic activities, the aim of this study was to study the effect of ethanolic extract of aerial parts of R. peregrina for the scavenging of free DPPH radicals and the inhibition of haloperidol-induced catalepsy in mice and reserpine-induced orofacial dyskinesia in rats. The extract exhibited significant antioxidant activity in a free radical DPPH assay with IC50 = 55.6 µg mL−1, which was very close to IC50 of ascorbic acid. The extract of R. peregrina (100 and 200 mg kg−1 intraperitoneally, i.p.) significantly inhibited haloperidol (1 mg kg−1 i.p.) – induced catalepsy in mice (p < 0.01). In rats, the extract (200 mg kg−1 i.p.) significantly (p < 0.01) inhibited the orofacial dyskinesia induced by intraperitoneal administration of reserpine (1 mg kg−1 on days 1, 3 and 5). This study demonstrates that R. peregrina has antioxidant activity and improves the dopaminergic function. Results therefore justify the development of further experiments to investigate the psychopharmacological profile of R. peregrina.

Piracetam reverses haloperidol-induced catalepsy in mice

To investigate the memory-enhancing drugs piracetam, vinpocetine, and ginkgo biloba for their ability to reduce catalepsy in mice treated with haloperidol. Haloperidol is a classic neuroleptic drug that induces motor abnormalities and cognitive impairment due to a blockade of dopamine D2 receptors in the striatum. Materials and methods: Catalepsy was induced by intraperitoneal haloperidol (2 mg/kg) administration. The drugs being tested were either administered intraperitoneally (IP) along with the dosage of haloperidol or 30 min prior to the introduction of the haloperidol. Catalepsy was measured using the bar test. Results: The administration of haloperidol (2 mg/kg, IP) resulted in significant catalepsy. Piracetam (in dosages of 50, 100, and 300 mg/kg) given IP at the time of haloperidol administration reduced the duration of catalepsy by 24.4%, 32.3%, and 48.2%, respectively. Piracetam given as a 30-min pretreatment reduced the duration of catalepsy by 59.5%, 72.3%, and 78.2%, respectively. Vinpocetine coadministered IP with haloperidol did not modify catalepsy, but given as a 30-min pretreatment, the drug increased catalepsy duration by 53.5%, 53.6%, and 65.1%, respectively. Ginkgo biloba coadministered IP with haloperidol at 25, 50, or 150 mg/kg increased catalepsy duration by 13.6%-17.1%. Ginkgo biloba given 30 min prior to haloperidol increased catalepsy duration by 29.1%, 35.1%, and 37.2%, respectively. Conclusion: The present study indicates that the nootropic drug piracetam reduces haloperidol-induced catalepsy in mice.

Effect of spironolactone on pain responses in mice.

The effects of spironolactone, a non-selective aldosterone antagonist, were examined on thermally-induced pain using the hot-plate and tail-flick tests, on chemogenic pain induced by intraplantar capsaicin, on electrically-induced pain, on visceral nociception induced by intraperitoneal acetic acid injection and on haloperidol-induced catalepsy in mice. Spironolactone significantly shortened response latency in the mouse tail-flick test but produced modest decreases in response latencies in the mouse hot plate test. The drug reduced the antinociceptive effect of tramadol in the hot plate test. Spironolactone in addition decreased nociceptive thresholds of electrically-induced pain in mice. In contrast, spironolactone elicited significant antinociceptive actions in the mouse acetic-acid-induced writhing assay and at doses of 20-160 mg/kg decreased capsaicin-induced chemogenic pain. Spironolactone at doses of 40 or 80 mg/kg reduced spontaneous activity and produced a significant impairment on the rotarod test in mice. The drug (10-80 mg/kg) increased the duration of catalepsy induced by haloperidol by 56.3-188.5 %. In conclusion, spironolactone increased pain behavior in a dose-dependent manner in models of thermal and electrical pain, but decreased inflammatory visceral pain due to intraperitoneal acetic acid and chemogenic pain due to intraplantar capsaicin. The effect of spironolactone on various types of pain needs further evaluation.

Caffeine withdrawal retains anticataleptic activity but Withania somnifera withdrawal potentiates haloperidol-induced catalepsy in mice

The previous study showed that chronic treatment with Withania somnifera extract (WS) inhibited haloperidol-induced catalepsy. It is suggested that caffeine and WS may be useful adjuvants in pharmacotherapy of Parkinson's disease. There are no studies on the effect of haloperidol on mice withdrawn from caffeine or W. somnifera. We therefore studied the effect of a single administration of standardised WS containing 5.1% total withanolides (WS, 30 or 100 mg kg−1 i.p.) and/or caffeine (3 mg kg−1 i.p.) and withdrawal from 6 days treatment with WS and/or caffeine, on haloperidol-induced catalepsy in albino mice. Single administration of both WS and caffeine, used either alone or in combination, significantly inhibited catalepsy. Mice withdrawn from caffeine significantly inhibited haloperidol-induced catalepsy, but mice withdrawn from WS showed increased catalepsy. The study indicated that withdrawal from WS does not retain anticataleptic activity, and caffeine but not WS may be a good adjuvant in pharmacotherapy of Parkinson's disease.

Synthesis of some urea and thiourea derivatives of naphtha[1,2-d]thiazol-2-amine as anti-Parkinsonian agents that cause neuroprotection against haloperidol-induced oxidative stress in mice

A series of N-(substituted phenyl)-N′-(naphtha[1,2-d]thiazol-2-yl)urea and thiourea derivatives were synthesized starting from N-naphthylthiourea. The structures were confirmed by spectral and elemental analyses. The newly synthesized compounds were found to possess anti-Parkinsonian and antioxidant activities. Anti-Parkinsonian activity was evaluated on haloperidol-induced catalepsy in mice by employing the standard bar test. All of the synthesized compounds ameliorated the catalepsy induced by haloperidol in mice. The most potent compounds (5, 6, 22, and 29) were selected for biochemical evaluation from the brain homogenate and were found to be effective in decreasing the elevated levels of malondialdehyde while restoring the cellular defense mechanisms such as glutathione content as well as glutathione peroxidase and superoxide dismutase activities in haloperidol-treated mice, suggesting the role of free radicals in the pathophysiology of haloperidol-induced catalepsy and possible antioxidant action of title compounds.

Caffeine withdrawal retains anticataleptic activity but Withania somnifera withdrawal potentiates haloperidol-induced catalepsy in mice

Caffeine withdrawal retains anticataleptic activity but Withania somnifera withdrawal potentiates haloperidol-induced catalepsy in mice

Glycyrrhiza glabra as an adjuvant in treatment of Parkinsonism and depression

The treatment of Parkinson's disease and depression is still far from satisfactory. The objective of the present study was to evaluate the potential of methanolic extract of Glycyrrhiza glabra (GGE) as an adjuvant in treatment of Parkinson's disease and depression. In acute study GGE (30 and 100mg/kg i.p.) significantly inhibited haloperidol-induced catalepsy in mice in dose dependent manner. Similar inhibitory effect of GGE was also observed in chronic study (15 days) indicating that there was no development of tolerance. The GGE reduced duration of catalepsy also. In mice treated with GGE (30mg/kg i.p.) for 6 days and given haloperidol on 7th day showed significantly (P&lt;0.05) diminished catalepsy and the higher dose completely inhibited catalepsy. This indicated its ability to retain the anticataleptic effect. Further GGE in both the doses increased apomorphine-induced sniffing indicating stimulation of Dopamine D1 receptor stimulation.

Evaluation of antiasthmatic activity ofCurculigo orchioidesgaertn. rhizomes

The ethanol extract of Curculigo orchioides was evaluated for antiasthmatic activity by using various in vitro and in vivo animal models. In vitro models like isolated goat tracheal chain preparation and isolated guinea pig ileum preparation were studied to know basic mechanism by which extract shows relaxant activity. The study showed that extract is effective against histamine-induced contraction. In isolated goat tracheal chain preparation and isolated guinea pig ileum preparation extract exhibits maximum relaxant effect (p< 0.01) against histamine at concentrations 100μg/ml and 25μg/ml respectively. Animal studies involved use of histamine induced bronchoconstriction in guinea pigs, egg albumin induced passive paw anaphylaxis in rats and haloperidol-induced catalepsy in mice. These studies showed significant (p< 0.01) protection at lower doses while further increase in the dose level showed reduced activity. Biochemical estimations in milk-induced total leukocytes count and milk-induced differential leukocyte count were also studied. In this study there was maximum increase in leucocytes and lymphocytes (99%) and maximum decrease in eosinophils up to 0% at dose 375mg/kg p.o. body weight was observed. The results of these studies indicated usefulness of ethanol extract of Curculigo orchioides in asthma.

Pharmacological Characterization of a Novel, Potent Adenosine A1 and A2A Receptor Dual Antagonist, 5-[5-Amino-3-(4-fluorophenyl)pyrazin-2-yl]-1-isopropylpyridine-2(1H)-one (ASP5854), in Models of Parkinson's Disease and Cognition

Central adenosine A(2A) receptor is a promising target for drugs to treat Parkinson's disease (PD), and the central blockade of adenosine A(1) receptor improves cognitive function. In the present study, we investigated the effect of a novel adenosine A(1) and A(2A) dual antagonist, 5-[5-amino-3-(4-fluorophenyl) pyrazin-2-yl]-1-isopropylpyridine-2(1H)-one (ASP5854), in animal models of PD and cognition. The binding affinities of ASP5854 for human A(1) and A(2A) receptors were 9.03 and 1.76 nM, respectively, with higher specificity and no species differences. ASP5854 also showed antagonistic action on A(1) and A(2A) agonist-induced increases of intracellular Ca(2+) concentration. ASP5854 ameliorated A(2A) agonist 2-[p-(2-carboxyethyl) phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS21680)- and haloperidol-induced catalepsy in mice, with the minimum effective doses of 0.32 and 0.1 mg/kg, respectively, and it also improved haloperidol-induced catalepsy in rats at doses higher than 0.1 mg/kg. In unilateral 6-hydroxydopamine-lesioned rats, ASP5854 significantly potentiated l-dihydroxyphenylalanine (L-DOPA)-induced rotational behavior at doses higher than 0.032 mg/kg. ASP5854 also significantly restored the striatal dopamine content reduced by 1-metyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment in mice at doses higher than 0.1 mg/kg. Furthermore, in the rat passive avoidance test, ASP5854 significantly reversed the scopolamine-induced memory deficits, whereas the specific adenosine A(2A) antagonist 8-((E)-2-(3,4-dimethoxyphenyl)ethenyl)-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione (KW-6002; istradefylline) did not. Scopolamine- or 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate) (MK-801)-induced impairment of spontaneous alternation in the mouse Y-maze test was ameliorated by ASP5854, whereas KW-6002 did not exert improvement at therapeutically relevant dosages. These results demonstrate that the novel, selective, and orally active dual adenosine A(1) and A(2A) receptors antagonist ASP5854 improves motor impairments, is neuroprotective via A(2A) antagonism, and also enhances cognitive function through A(1) antagonism.

Evaluation of the antioxidant potential of NR-ANX-C (a polyherbal formulation) and its individual constituents in reversing haloperidol-induced catalepsy in mice

<b>Objective</b> : To evaluate the possible role of the antioxidant activity of the polyherbal formulation, NR-ANX-C and its individual components in reversing haloperidol-induced catalepsy in Swiss albino mice.<b><br>Materials and Methods</b> : Catalepsy was induced with haloperidol (1 mg/kg <i>i.p</i>) in 13 groups of male albino mice (<i>n</i> = 6 / group). Three groups received NR-ANX-C (10, 25, 50 mg/kg), three groups received <i>Withania somnifera</i> (1.7, 4.25, 8.5 mg/kg), another three groups <i>Ocimum sanctum</i> (1.7, 4.25, 8.5 mg/kg), three other groups <i>Camellia sinensis</i> (3.4, 8.5, 17 mg/kg) and one group received the vehicle (1% <i>Gum acacia</i>) orally, 30 minutes prior to haloperidol administration, for a duration of seven days. Animals were sacrificed on the seventh day and superoxide dismutase (SOD) activity was estimated in the brain.<b><br>Results</b> : A significant (<i>P </i>< 0.01) reduction in the cataleptic scores was observed in all the drug-treated groups as compared to the control, with maximum reduction in the NR-ANX-C 25 mg/kg group. Similarly, a reduction in SOD activity was observed in the NR-ANX-C-, <i>O. sanctum-</i> and the <i>W. somnifera</i>-treated groups. An increase in SOD activity was observed in the <i>C. sinensis</i>-treated groups.<br><b> Conclusion</b> : With the exception of <i>C. sinensis</i>, the antioxidant potential of NR-ANX-C and its individual constituents has contributed to the reduction in the oxidative stress and the catalepsy induced by haloperidol administration.