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PubMed1996

Azirino[1, 2-d][1, 4]benzodiazepine derivatives and related 1,4-benzodiazepines as anticonvulsant agents in DBA/2 mice.

1. The behavioral and anticonvulsant effects of several 1, 4-benzodiazepine (BDZ) and azirino[1,2-d] [1, 4]benzodiazepine (ABDZ) derivatives were studied after intraperitoneal administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. 2. The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation (109 dB, 12-16 kHz) in animals placed singly under a Perspex dome. 3. The 1,4-benzodiazepines were generally more potent than the related azirino[1,2-d] [1,4]benzodiazepine derivatives which, however, showed a remarkable anticonvulsant activity. The rank order of potency for anticonvulsant activity was flunitrazepam > diazepam > pinazepam > ABDZ5 > ABDZ4 > prazepam > halazepam > ABDZ1 > ABDZ3 > camazepam > ABDZ6 > ABDZ2. 4. The impairment of locomotor performance following intraperitoneal (IP) administration of the aforementioned derivatives was also evaluated by means of rotarod test. The rank order of potency for impairment of coordinated motor movements was pinazepam > flunitrazepam > diazepam > ABDZ5 > prazepam > halazepam > ABDZ4 > ABDZ3 > ABDZ1 > camazepam > ABDZ2 = ABDZ6. 5. A hypothermic activity was observed after the highest doses of the benzodiazepines studied. 6. The potency of various 1,4-benzodiazepines and azirino[1, 2-d][1,4]benzodiazepines as inhibitors of specific [3H]flumazenil binding to membranes from cerebellum or cortex was evaluated. In general, they inhibited [3H]flumazenil binding at the micromolar range. However, some ABDZ derivatives, although active as anticonvulsants, failed to displace [3H]flumazenil. 7. The azirino[1,2-d] [1,4]benzodiazepine derivatives are more lipophilic than the related benzodiazepines, but the different degree of anticonvulsant activity and impairment of coordinated motor movements cannot be directly related to the lipophilicity of the compounds studied. 8. The pharmacologic actions of ABDZ4 and ABDZ5, which appeared as the most potent anticonvulsants of the azirino[1,2-d] [1,4]benzodiazepine derivatives, were significantly reduced by treatment with flumazenil (8.24 mumol/kg IP) suggesting a clear involvement of benzodiazepine mechanisms in the anticonvulsant activity of these compounds or their metabolites. 9. The anticonvulsant activity of ABDZ4 and ABDZ5 was also evaluated against seizures induced by the two beta-carbolines, methyl beta-carboline-3-carboxylate (beta-CCM) and methyl6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), in DBA/2 mice. Both ABDZ4 and ABDZ5 gave better protection against the seizures induced by beta-CCM than DMCM, suggesting a preferential action on BDZ1 receptors.

Acoustic Stimulation↗
PubMed2005

TPA023 [7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine], an agonist selective for alpha2- and alpha3-containing GABAA receptors, is a nonsedating anxiolytic in rodents and primates.

7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) is a triazolopyridazine that binds with equivalent high (subnanomolar) affinity to the benzodiazepine binding site of recombinant human GABA(A) receptors containing an alpha1, alpha2, alpha3, or alpha5 subunit but has partial agonist efficacy at the alpha2 and alpha3 subtypes and essentially antagonist efficacy at the alpha1 and alpha5 subtypes. In rats, TPA023 gave time- and dose-dependent occupancy after oral dosing, with 50% occupancy corresponding to a dose of 0.42 mg/kg. It has anxiolytic-like activity in unconditioned (elevated plus maze) and conditioned (fear-potentiated startle and conditioned suppression of drinking) rat models of anxiety with minimum effective doses (MED; 1-3 mg/kg) corresponding to 70 to 88% occupancy. However, there was no appreciable sedation in a response sensitivity (chain-pulling) assay at a dose of 30 mg/kg, resulting in 99% occupancy. Similarly, TPA023 was robustly anxiolytic in the squirrel monkey conditioned emotional response assay, with a MED of 0.3 mg/kg, but did not produce any sedation in a lever-pressing test of sedation even at 10 mg/kg. TPA023 produced no impairment in performance in the mouse Rotarod assay, and there was only a mild interaction with ethanol. In addition to anxiolytic-like efficacy, TPA023 had anticonvulsant activity in a mouse pentylenetetrazole seizure model. Finally, TPA023 did not cause precipitated withdrawal in mice treated for 7 days with the nonselective agonist triazolam, nor did N-methyl-beta-carboline-3-carboxamide (FG 7142) precipitate withdrawal in mice treated for 7 days with TPA023. In summary, the novel alpha2/alpha3-selective efficacy profile of TPA023 translates into a nonsedating anxiolytic profile that is distinct from nonselective agonists.

Acoustic Stimulation↗
PubMed2004

Antagonism at metabotropic glutamate 5 receptors inhibits nicotine- and cocaine-taking behaviours and prevents nicotine-triggered relapse to nicotine-seeking.

Previous studies in metabotropic glutamate 5 receptor (mGlu5 receptor) deficient mice have indicated the importance of this receptor in the self-administration of cocaine and locomotor sensitisation to this stimulant. Both ionotropic and metabotropic receptors have been implicated in drug-seeking and drug-taking behaviours, but the specific role of each subtype of metabotropic glutamate receptors (mGlu receptors) is still unknown. In the present series of experiments we further investigated the role of mGlu5 receptors on nicotine, cocaine- and food-taking behaviour. We also investigated the effects of the mGlu5 receptor antagonist MPEP (2-methyl-6-(phenylethynyl)pyridine) on the acute locomotor activating effects of nicotine, the expression of sensitisation to its repeated, intermittent administration, and nicotine-triggered relapse to nicotine-seeking behaviour. The results indicate that MPEP treatment reduced nicotine-induced drug-seeking behaviour in a model of nicotine-triggered relapse to nicotine seeking. Furthermore, MPEP decreased both nicotine and cocaine self-administration without affecting food self-administration under similar schedules of reinforcement. Finally, MPEP reduced both the acute locomotor stimulant effects of nicotine as well as the expression of behavioural sensitisation to its repeated administration. Although the intravenous administration of MPEP at 1 and 10 mg/kg transiently reduced spontaneous locomotor activity during the first 25 min post-administration, we also demonstrated that performance on the accelerating rotarod was not affected when MPEP was given 5 and 30 min prior to the test. Altogether, the present findings strengthen the hypothesis that selective antagonism at mGlu5 receptors may be a new potential pharmacotherapeutic approach for the treatment of drug dependence and addiction.

Animals↗
PubMed2006

Comparison of incremental and accelerating protocols of the rotarod test for the assessment of motor deficits in the 6-OHDA model.

The rotarod test, in which animals must balance on a rotating drum, is widely used to assess motor deficit in neurodegenerative disease models in rodents. Performance is measured by the duration that an animal stays on the rod as a function of drum speed. Two different protocols are widely used, incremental fixed speeds or an accelerating protocol, but there is little information on their equivalence or the relative power, reliability and sensitivity of the two protocols. The present study was undertaken to compare the incremental fixed-speed and accelerating rotarod protocols on two different lesions of the ascending forebrain dopamine pathways. Three groups of rats were used, controls, rats with 6-OHDA lesions of nigrostriatal bundle, and rats with terminal 6-OHDA lesions within the striatum. Rats were tested at different time points after the lesion. We report that whereas the incremental protocol is more sensitive to detect the presence of a lesion, the accelerating protocol provides a more discriminative test to correlate motor deficits against lesion size.

Acceleration↗
PubMed1996

1,4-Benzodiazepine derivatives as anticonvulsant agents in DBA/2 mice.

1. The behavioural and anticonvulsant effects of 10 1,4-benzodiazepine derivatives were studied after intraperitoneal administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. 2. The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation (109 dB, 12-16 kHz) in animals placed singly under a perspex dome. The rank order of potency for anticonvulsant activity was alprazolam > clonazepam > flunitrazepam > diazepam > pinazepam > desmethyldiazepam > oxazepam > prazepam > halazepam > camazepam. 3. The impairment of locomotor performance following IP administration of the above reported derivatives was also evaluated by means of the rotarod test. 4. Hypothermic activity was observed after the highest doses of the benzodiazepines studied. 5. The potency of various 1,4-benzodiazepines as inhibitors of specific [3H] flumazenil binding to membranes from cerebellum or cortex was evaluated. In general, 1,4-benzodiazepines were active as anticonvulsants at micromolar range and inhibited [3H] flumazenil binding at nanomolar range. 6. The different degree of anticonvulsant activity and impairment of coordinated motor movements cannot be directly related to the benzodiazepine binding affinity or to the lipophilicity of the compounds studied.

Animals↗
PubMedDate not supplied

Neurotoxicity testing during long-term studies.

Several tests and methods for the investigation of neurotoxicity were performed with female Wistar rats for up to 187 days. The methods were validated by testing 10 rats treated with beta,beta'-iminodipropionitrile (IDPN) and 10 control rats. Cage side observation of the animals revealed signs of altered behavior and motor dysfunction of the IDPN-treated rats. Results of a neuromuscular screen indicated changes in gait, righting reflex, grip strength and performance of the negative geotropism test. Investigation of the animals in activity monitors and on the accelerating rotarod showed changes of several parameters. The motor nerve conduction velocity, measured 6 months after the first treatment, was reduced by 6.7 meters per second in the IDPN group compared to controls. From the results of the tests it can be concluded that the methods chosen can be used during long-term studies but may be most useful for animals not older than 12 months.

Animals↗
PubMed2003

Anxiolytic-like and antidepressant-like activities of MCL0129 (1-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine), a novel and potent nonpeptide antagonist of the melanocortin-4 receptor.

We investigated the effects of a novel melanocortin-4 (MC4) receptor antagonist,1-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine (MCL0129) on anxiety and depression in various rodent models. MCL0129 inhibited [(125)I][Nle(4)-D-Phe(7)]-alpha-melanocyte-stimulating hormone (alpha-MSH) binding to MC4 receptor with a K(i) value of 7.9 nM, without showing affinity for MC1 and MC3 receptors. MCL0129 at 1 microM had no apparent affinity for other receptors, transporters, and ion channels related to anxiety and depression except for a moderate affinity for the sigma(1) receptor, serotonin transporter, and alpha(1)-adrenoceptor, which means that MCL0129 is selective for the MC4 receptor. MCL0129 attenuated the alpha-MSH-increased cAMP formation in COS-1 cells expressing the MC4 receptor, whereas MCL0129 did not affect basal cAMP levels, thereby indicating that MCL0129 acts as an antagonist at the MC4 receptor. Swim stress markedly induced anxiogenic-like effects in both the light/dark exploration task in mice and the elevated plus-maze task in rats, and MCL0129 reversed the stress-induced anxiogenic-like effects. Under nonstress conditions, MCL0129 prolonged time spent in the light area in the light/dark exploration task and suppressed marble-burying behavior. MCL0129 shortened immobility time in the forced swim test and reduced the number of escape failures in inescapable shocks in the learned helplessness test, thus indicating an antidepressant potential. In contrast, MCL0129 had negligible effects on spontaneous locomotor activity, Rotarod performance, and hexobarbital-induced anesthesia. These observations indicate that MCL0129 is a potent and selective MC4 antagonist with anxiolytic- and antidepressant-like activities in various rodent models. MC4 receptor antagonists may prove effective for treating subjects with stress-related disorders such as depression and/or anxiety.

Animals↗
PubMed2001

Hyperactivity, neuromotor defects, and impaired learning and memory in a mouse model for metachromatic leukodystrophy.

Deficiency of arylsulfatase A (ASA) causes the autosomal recessive lipidosis, metachromatic leukodystrophy (MLD). Performance on tests of activity, motor ability and learning/memory was assessed in ASA-deficient mice and normal controls at 3, 6 and 12 months-of-age. ASA-deficient mice showed consistently increased cage activity in all age groups, whereas open field activity was increased only in the 3-month-old group. Motor coordination and equilibrium, as tested in the rotarod test, was impaired in 12-month-old ASA-deficient mice. Passive avoidance learning was tested in the step-through box. Performance on this test was impaired in the 12-month-old group only. Spatial learning and memory abilities were tested in the Morris water maze. Six-month-old ASA-deficient mice displayed slightly impaired hidden-platform acquisition performance. Three-month-old animals, on the other hand, did not show any acquisition or retention defect on this task, notwithstanding significantly reduced swimming velocity. Acquisition training, both in the hidden- and visible-platform conditions of the Morris water maze, and retention performance during the probe trials were impaired in 12-month-old ASA-deficient mice. The hyperactivity, motor incoordination and slowing, and the age-related learning/memory defects, reported here in ASA-deficient mice, may relate to the decline of neuromotor and cognitive functions in MLD patients, and could be used as correlative or outcome measures in the study of MLD pathophysiology and treatment.

Age Factors↗
PubMed1991

Comparison of the antinociceptive and motor effects of intrathecal opioid agonists in the rat.

This study compared the antinociceptive and motor effects produced by intrathecal administration of selective mu-, delta-, and kappa-opioid receptor agonists in the rat. Changes in nociceptive threshold were measured using the Randall-Selitto paw-withdrawal test and changes in motor coordination were evaluated using the rotarod treadmill test. Each opioid agonist produced statistically significant, dose-dependent increases in mechanical nociceptive thresholds compared to vehicle controls. In the motor coordination studies, DAMGO and DPDPE, but not U50,488H, produced statistically significant decreases in rotarod performance scores compared to vehicle controls. The results of these studies suggest that motor side-effects produced by opioid agonists need to be considered when interpreting the results of antinociceptive tests that are dependent on a normally functioning motor system.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2002

Evaluation of antidepressant-related behavioral responses in mice lacking the serotonin transporter.

Inhibition of the serotonin transporter (5-HTT) is a principal initial target of many antidepressants. However, the contribution of the 5-HTT to their therapeutic efficacy is incompletely understood. We utilized a targeted gene mutation approach to examine the role of the 5-HTT in the behavioral actions of antidepressants. The 5-HTT mutation was bred onto two separate genetic backgrounds, C57BL/6J and 129S6. On a preliminary screen for gross physical, neurological and behavioral functions, all measures were normal with the exception that 5-HTT -/- mice on the C57BL/6J background showed increased body weight and poor rotarod performance, and 5-HTT -/- mice on the 129S6 background showed reduced neuromuscular strength. On the tail suspension test, 5-HTT -/- mice on the 129S6 background showed a baseline antidepressant-like reduction in immobility. In contrast, the same mice showed increased immobility in the forced swim test, possibly due to compromised neuromuscular strength. 5-HTT -/- mice on the C57BL/6J background showed no baseline antidepressant-related phenotype on either test. The behavioral effects of three antidepressants were tested in 5-HTT mutant mice (C57BL/6J background) in the tail suspension test. The anti-immobility effects of the serotonin reuptake inhibitor, fluoxetine (30 mg/kg), were abolished in 5-HTT -/- mice, confirming that the 5-HTT gene is required for the behavioral effects of fluoxetine. In contrast, 5-HTT-/- mice retained sensitivity to the anti-immobility effects of the norepinephrine reuptake inhibitor, desipramine (20 mg/kg), and the mixed serotonin/norepinephrine reuptake inhibitor, imipramine (25 mg/kg). 5-HTT knockout mice provide a valuable tool for delineating the neuropsychopharmacological actions of antidepressants.

Animals↗
PubMed1979

Tolerance to amphetamine-induced impairment of rotarod performance in rats.

Acute administration of d-amphetamine sulfate (30 mg/kg, i.p.) caused muscle weakness and 80% failure in rotarod performance in rats. The incidence of performance failure progressively decreased to 30% in animals receiving d-amphetamine and tested daily for 8 days. A similar progressive reduction in performance impairment was observed in animals receiving d-amphetamine for 3, 5, or 7 days (12.5%) and evaluated only once after the last dose. The tolerance is attributable to a physiological or biochemical rather than learning phenomenon.

Animals↗
PubMed1999

Analgesic effect of tianeptine in mice.

The effects of tianeptine, a novel and unusual tricyclic antidepressant drug, on tail-flick and hot-plate tests, which are two thermal analgesia evaluating methods, have been investigated in mice. Tianeptine (5 and 10 mg/kg), para-chlorophenylalanine (pCPA) (100 mg/kg) and a combination of pCPA and tianeptine (10 mg/kg) or saline were injected to mice intraperitoneally. pCPA (100 mg/kg) was injected 24 h before tianeptine or saline treatment when it was combined with tinaeptine (10 mg/kg) or tested alone. The tail-flick latencies and hot-plate reaction times of the mice were measured between 15th and 180th minutes following injections. Tianeptine (10 mg/kg) exhibited a significant antinociceptive activity that could be measured by both tests as compared to groups which were treated with saline or pCPA alone between 15th and 180th min of the observation period. The lower dose of tianeptine (5 mg/kg) or pCPA (100 mg/kg) did not produce any significant changes on tail-flick latency or hot-plate reaction time of the mice. However, pretreatment with pCPA completely blocked the antinociceptive effect induced by tianeptine (10 mg/kg) in both tests used in the present study. Furthermore, tianeptine (10 mg/kg) did not cause any significant impairment effects on rotarod performance of the mice. Our results suggested that tianeptine has a prominent thermal antinociceptive activity in mice and that increased serotonergic activity may be responsible for the analgesic effect of tianeptine.

Analgesics↗
PubMed2003

Treatment of traumatic brain injury in adult rats with intravenous administration of human bone marrow stromal cells.

OBJECTIVE: We investigated the effect of human bone marrow stromal cells (hMSCs) administered intravenously on functional outcome after traumatic brain injury in adult rats. METHODS: hMSCs were harvested from three human donors. A controlled cortical impact was delivered to 27 adult male rats to induce traumatic brain injury, and 24 hours after injury, hMSCs were injected into the tail veins of the rats (n = 18). These rats were divided into two groups: Group 1 was administered 1 x 10(6) hMSCs, and Group 2 was administered 2 x 10(6) hMSCs. Group 3 (control) rats received saline intravenously. Neurological function was evaluated according to the rotarod test and modified neurological severity score. All rats were killed 1 month after injury, and immunohistochemical staining was performed on the brain sections to identify donor hMSCs. To study the phenotypic differentiation of hMSCs, coronal brain sections were stained for neuronal (Tuj1) and astrocytic (glial fibrillary acidic protein) markers. RESULTS: Treatment with 2 x 10(6) hMSCs significantly improved the rats' functional outcomes (P < 0.05). The transplanted cells successfully migrated into injured brain and were preferentially localized around the injury site. Some of the donor cells also expressed the neuronal and astrocytic markers. CONCLUSION: These data suggest that hMSCs may be a potential therapy for patients who have sustained traumatic brain injuries.

Animals↗
PubMed1988

Interaction of two barbiturates and an antihistamine on body temperature and motor performance of mice.

As an example for a drug combination used as a sedative (Vesparax) the actions of secobarbital (S), brallobarbital (B) and the antihistamine etodroxizine (E) were studied in mice after single and concomitant oral application. S and B caused a dose-dependent increase of exploratory locomotor performance enclosing a short period of locomotor depression. Such excitatory effect was suppressed by concomitant application. E produced a decrease in locomotion and--when added to S and B--enhanced their sedative effects. Explorative rearing was suppressed by low doses of S and B, by B, by E, and by all the combinations, whereas high single doses of S and B (20 mg/kg and 25 mg/kg, resp.) caused a triphasic temporal pattern. Motor coordination was investigated by means of fixed-bar and rotarod procedures. Increasing doses of S and B impaired motor performance within a small dose range. In concomitant applications rotarod performance revealed a dose-additive synergism whereas the effect was moderately superadditive in the fixed-bar test. Neither in single applications nor in combinations E showed any effects. Rectal temperature was poorly affected by the single drugs, but hypothermia was strongly enhanced by concomitant application of S and B and further potentiated by addition of E. The results suggest that responses to combinations of drugs even belonging to the same category cannot sufficiently be deduced from the single components alone.

Animals↗
PubMed1999

Pharmacological studies on a rat model of trigeminal neuropathic pain: baclofen, but not carbamazepine, morphine or tricyclic antidepressants, attenuates the allodynia-like behaviour.

Trigeminal neuralgia is an example of an extreme form of neuropathic pain and continues to be a real therapeutic challenge. Although the pathophysiology of the disorder is uncertain, vascular compression of the trigeminal root resulting in damage to primary afferent neurons is thought to play a major role in the generation of pain. In the present study, we have used a recently developed rat model of trigeminal neuropathic pain, where the neuropathy is produced by a chronic constriction injury of the infraorbital branch of the trigeminal nerve (CCI-ION), and for the first time studied the effects of various pharmacological treatments on this purely sensory model of neuropathic pain. Rats with a CCI-ION consistently display a series of spontaneous behavioural abnormalities that may be indicative of trigeminal paraesthesias/dysesthesias. A hyper-responsiveness of the territory of the ligated infraorbital nerve to light mechanical stimulation with von Frey hairs also develops at 7-12 days after the injury. Pharmacological studies indicated that the mechanical hyper-responsiveness could be reversibly abolished by local injections of alphacaine into the close proximity of the injured nerve. The allodynia-like behaviour was resistant to i.v. morphine. Similarly, single and repeated injections (using the respective T 1/2 as an interval) of tricyclic antidepressants amitriptyline and clomipramine were devoid of effects on the mechanical allodynia-like behaviour. Carbamazepine was effective only after doses (> or =10 mg/kg s.c.) that already caused disturbances in motor co-ordination in the rotarod test. Repeated injections of baclofen (3 mg/kg s.c.) partially alleviated the mechanical allodynia-like behaviour without effects on rotarod performance. The partial anti-allodynic effect of a single injection (5 mg/kg) of baclofen, which was already accompanied by slight motor disturbances, could be antagonized by CGP35348, a selective GABA(B)-receptor antagonist. Functional deficits in the GABAergic system may play an important role in the pathogenesis of this purely sensory rat model of trigeminal neuropathic pain.

Analgesics, Non-Narcotic↗
PubMed2003

Cellular and behavioural effects of the adenosine A2a receptor antagonist KW-6002 in a rat model of l-DOPA-induced dyskinesia.

We have examined the ability of KW-6002, an adenosine A2a antagonist, to modulate the dyskinetic effects of L-DOPA in 6-hydroxydopamine-lesioned rats. In animals rendered dyskinetic by a previous course of L-DOPA treatment, KW-6002 did not elicit any abnormal involuntary movements on its own, but failed to reduce the severity of dyskinesia when coadministered with L-DOPA. A second experiment was undertaken in order to study the effects of KW-6002 in L-DOPA-naive rats. Thirty-five animals were allotted to four groups to receive a 21-day treatment with: (i) KW-6002 (10 mg/kg/day); (ii) L-DOPA (6 mg/kg/day) i.p.; (iii) KW-6002 plus L-DOPA (same doses as above) or (iv) vehicle. Chronic treatment with KW-6002-only produced a significant relief of motor disability in the rotarod test in the absence of any abnormal involuntary movements. Combined treatment with L-DOPA and KW-6002 improved rotarod performance to a significantly higher degree than did each of the two drugs alone. However, this combined treatment induced dyskinesia to about the same degree as did L-DOPA alone. In situ hybridization histochemistry showed that KW-6002 treatment alone caused an approximately 20% reduction in the striatal levels of preproenkephalin mRNA, whereas neither the coadministration of KW-6002 and L-DOPA nor L-DOPA alone significantly altered the expression of this transcript in the dopamine-denervated striatum. Either alone or in combination with L-DOPA, KW-6002 did not have any modulatory effect on prodynorphin mRNA expression or FosB/DeltaFosB-like immunoreactivity in the dopamine-denervated striatum. These results show that monotreatment with an adenosine A2a receptor antagonist can relieve motor disability without inducing behavioural and cellular signs of dyskinesia in rats with 6-hydroxydopamine lesions. Cotreatment with KW-6002 and L-DOPA potentiates the therapeutic effect but not the dyskinesiogenic potential of the latter drug.

Animals↗
PubMed2005

Granulocyte colony-stimulating factor induces sensorimotor recovery in intracerebral hemorrhage.

Granulocyte colony-stimulating factor (G-CSF) has been used in the treatment of neutropenia in hematologic disorders. The neuroprotective and anti-inflammatory effects of G-CSF were reported in various neurological disease models. In this study, we examined whether G-CSF induces functional recovery after intracerebral hemorrhage (ICH). ICH was induced using collagenase injection in adult rats. Either G-CSF (50 microg/kg, i.p.) or saline was given from 2 h after ICH and every 24 h for 3 days. 72 h after ICH induction, the rats were sacrificed for histological analysis and measurement of brain edema. Behavioral tests were performed before and 1, 7, 14, 21, 28, and 35 days after ICH. We also measured the blood-brain barrier (BBB) permeability using Evans blue dye injection method. G-CSF-treated rats recovered better on rotarod and limb placing tests, starting from 14 days throughout 5 weeks after ICH. The brain water content and BBB permeability of G-CSF-treated group decreased in the lesioned hemispheres compared with those of ICH-only group. In G-CSF-treated group, the number of TUNEL+, myeloperoxidase+, and OX42+ cells was smaller than that of ICH-only group in the periphery of hematoma. These findings suggest that G-CSF induces long-term sensorimotor recovery after ICH with reduction of brain edema, inflammation, and perihematomal cell death.

Animals↗
PubMed2004

Are age-related deficits in balance performance mediated by time of day in a prosimian primate (Microcebus murinus)?

We examined the effects of age and time of day on balance performance in the gray mouse lemur (Microcebus murinus) in relation to body temperature variations. Groups of young, adult and aged animals were entrained to either short (SP, L/D 10/14) or long photoperiod (LP, L/D 14/10) and tested in the accelerating Rotarod at three phases of their light/dark cycle (beginning and end of the light phase, beginning of the dark phase). In addition, for each test, rectal temperature (Tr) was measured. Under LP, whatever the test phase, this primate showed a clear age-related decrease in balance performance. Under SP, no significant age-related decline in balance could be detected. Whatever the photoperiod, an effect of time of day on balance performance could only be seen in adults, with better performances at the beginning of the dark phase when Tr values were higher. Under LP, daily variations of both balance performance and Tr disappeared with advancing age. Consequently, age differences were substantially greater when testing was conducted during the dark phase of the light/dark cycle. The time of day effect on balance performance and the loss of daily variations with age suggest the influence of age-related changes within the biological clock.

Age Factors↗