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PubMed1992

Neuroprotective actions of riluzole in rodent models of global and focal cerebral ischaemia.

Riluzole (2 amino 6-trifluoromethoxybenzothiazole), when administered at 4 and 8 mg/kg i.p., 0.5, 4.5, 24 and 28 h after the initiation of ischaemia, significantly reduced the prevalence of slow wave, and increased the proportion of higher frequency activity seen in the quantified electrocorticogram (ECoG), during the weeks that followed a 6 min bilateral occlusion of the common carotid arteries in the Mongolian gerbil. In focal ischaemia, provoked in Fischer rats following the occlusion of the middle cerebral artery, administration of riluzole (8 mg/kg) at 30 min and 24.5 h post occlusion significantly reduced the volume of infarcted cortex. These activities of riluzole could be related to its inhibition of sodium channel activity, which in turn inhibits glutamate release.

Animals↗
PubMed1984

L-pyroglutamate: an alternate neurotoxin for a rodent model of Huntington's disease.

Intrastriatal injections of L-Pyroglutamate (L-PGA) in mice produced behavioral and neuropathological effects that resemble in part the kainate-injected rat striatal model of Huntington's Disease (HD). The behavioral responses induced after unilateral injections of L-PGA included circling, postural asymmetry of head and trunk and possible dyskinesias. The neuropil in the injected striatum contained dilated profiles, degenerating neurons and oligodendroglia, and numerous phagocytic microglial-like cells. A dose response relation existed. The size of the lesion (expressed as a percent volume of the striatum destroyed) ranged from 1 +/- 0.18% at 0.02 mumoles to 20.2 +/- 3.97% at 200 mumoles L-PGA (pH = 7.3). L-PGA is a weak neurotoxin when compared to kainic acid. Several factors raise interest in the possible role of L-PGA in HD, including the recently reported elevated plasma levels of L-PGA in some HD patients, and these considered in the discussion.

Animals↗
PubMedDate not supplied

Cefpirome, alone and in combination with gentamicin for enterococcal pyelonephritis in the rodent model.

The in vitro and in vivo activity of cefpirome (CF) against Enterococcus faecalis GK strain was examined. The ratio of minimal inhibitory to bactericidal concentration (MIC/MBC) values in microgram/ml were (a) ampicillin 0.8/1.5; (b) gentamicin 2/25; (c) vancomycin, 0.8/50; and (d) CF, 8/32. A time-kill study using 10(7) organisms per milliliter showed a drop of 3 logs10 at 4 hr in the tube containing cefpirome (10 micrograms/ml) as well as the tube containing cefpirome (5 micrograms/ml) plus gentamicin (GM) (2 micrograms/ml), as compared to the control and the tube containing GM at 4 micrograms/ml. At 8 and 24 hr, however, regrowth to control levels occurred. Of this enterococcal strain consisting of 10(8) organisms, 1 ml was then injected intravenously by tail vein into 150 male Wistar rats weighing 120 g each. Eleven days after injection, 10 rats were killed and the remaining ones were randomized into four treatment groups: (a) untreated control; (b) BM, 0.9 mg; (c) CF, 10 mg; and (d) CF + GM. The rats received the injections intramuscularly twice daily. At least 10 rats from each group were killed for quantitative kidney cultures at 1, 2, and 4 weeks after start of therapy. At the end of 4 weeks of therapy, the results were significantly better in the combination group compared to the other three groups.

Ampicillin↗
PubMedDate not supplied

Phenobarbital treatment of status epilepticus in a rodent model.

Although phenobarbital is frequently used in the treatment of status epilepticus, little has been published concerning the dose or serum concentration which effectively control adult status. We studied the efficacy of phenobarbital in controlling status in a rat model which induces generalized tonic-clonic seizures (GTCS) which respond to other drugs at serum concentrations similar to those reported to be effective in human status. We found that phenobarbital is rapidly absorbed following intraperitoneal injection, but entry into brain is delayed. Brain entry was facilitated during uncontrolled status epilepticus. The ED50 values for control of seizures in this model rose in a dose-dependent manner for increasing levels of seizure control, from 14.2 mg/kg for control of GTCS to 76.6 mg/kg for control of all motor and electrographic ictal activity. Raising serum concentrations above the 20 micrograms/ml required to control GTCS produced increasingly better control of the various types of ictal activity seen in this model.

Animals↗
PubMed2004

Rodent models for the study of therapy against flavivirus infections.

Flaviviruses cause a variety of diseases including (meningo)encephalitis and hemorrhagic fevers. There is no specific antiviral therapy available for the treatment of infections with flaviviruses and such therapy should be urgently developed. Small animal models that are reminiscent of the disease in man will be instrumental to identify therapeutic strategies against flavivirus infections. Here we review models in mice and hamsters that may be used to assess the efficacy of novel antiviral strategies against flavivirus infections.

Animals↗
PubMed2005

Oxidative stress and pro-apoptotic conditions in a rodent model of Wilson's disease.

Wilson's disease (WD) is an inherited disorder, characterized by selective copper deposition in liver and brain, chronic hepatitis and extra-pyramidal signs. In this study, we investigated changes of biochemical markers of oxidative stress and apoptosis in liver, striatum and cerebral cortex homogenates from Long-Evans Cinnamon (LEC) rats, a mutant strain isolated from Long Evans (LE) rats, in whom spontaneous hepatitis develops shortly after birth. LEC and control (LE) rats at 11 and 14 weeks of age were used. We determined tissue levels of glutathione (GSH/GSSG ratio), lipid peroxides, protein-thiols (P-SH), nitric oxide metabolites, activities of caspase-3 and total superoxide-dismutase (SOD), striatal levels of monoamines and serum levels of hepatic amino-transferases. We observed a decrease of protein-thiols, GSH/GSSG ratio and nitrogen species associated to increased lipid peroxidation in the liver and striatum - but not in the cerebral cortex - of LEC rats, accompanied by dramatic increase in serum amino-transferases and decrease of striatal catecholamines. Conversely, SOD and caspase-3 activity increased consistently only in the cortex of LEC rats. Hence, we assume that enhanced oxidative stress may play a central role in the cell degeneration in WD, at the main sites of copper deposition, with discrete pro-apoptotic conditions developing in distal areas.

Analysis of Variance↗
PubMed2004

Behavioral sensitization to different dopamine agonists in a parkinsonian rodent model of drug-induced dyskinesias.

Repeated treatment with dopamine (DA) receptor agonists strongly potentiates contralateral turning behavior due to selective stimulation of D1 or D2-class receptors in 6-hydroxydopamine (6-OHDA)-lesioned rats. This phenomenon, referred to as sensitization, is believed to be related to the motor response complications (dyskinesias, on-off states) that occur during chronic administration of levodopa in Parkinson's disease patients. In recent years a new method for the evaluation of abnormal involuntary movements (AIMs) secondary to dopaminergic stimulation in 6-OHDA-lesioned rats was described. These AIMs resemble dyskinesias as seen in parkinsonian patients under levodopa therapy. Our objective was to evaluate the effects of repeated treatment with different regimes of DA agonists on turning behavior and on an AIMs scale in 6-OHDA lesioned rats, with the aim of discriminating between drugs with different dyskinesia-inducing potential. In addition, we explored the effects of a previous exposure to a DA agonist (priming) on the behavioral response to the subsequent administration of a DA agonist with the same or different pharmacologic profile. Our results show that in apomorphine-treated rats, rotational behavior and AIMs run a parallel course of enhancement, while in those receiving quinpirole there is a dissociation, suggesting that they could be mediated by different mechanisms. The finding of a significant priming effect on subsequent testing of 6-OHDA lesioned rats should be borne in mind as the use of these pharmacological tests in the screening of well lesioned animals could lead to an erroneous interpretation of further results on dyskinesias and rotational behavior.

Analysis of Variance↗
PubMed2005

Evaluation of the effects of lamotrigine, valproate and carbamazepine in a rodent model of mania.

Bipolar disorder is a psychiatric condition characterised by episodes of mania, depression, and underlying mood instability. Anticonvulsant drugs have an established place in the treatment of the disorder, but identifying novel drugs in this class is complicated by the absence of validated animal models. We have evaluated the efficacy of three anticonvulsant mood stabilising drugs (lamotrigine, valproate, and carbamazepine) in a model of mania, in which hyperactivity is induced by the combination of D-amphetamine and chlordiazepoxide. All three drugs were effective at preventing the hyperactivity. Lower doses of valproate and carbamazepine were required to prevent hyperactivity compared to doses required to block tonic-clonic seizures induced by pentylenetetrazole. Lamotrigine was equipotent in the two models. However, the complex pharmacology of the D-amphetamine/chlordiazepoxide model means that there may be several mechanisms by which hyperactivity can be reduced, and these may have more or less relevance to the treatment of bipolar disorder. To address this issue, we also evaluated effects of the three anticonvulsants on baseline locomotion, on activity in the presence of chlordiazepoxide alone, or on activity induced by D-amphetamine alone. Based on the results, we propose that hyperactivity induced by D-amphetamine/chlordiazepoxide may arise through dopaminergic drive coupled with disinhibition caused by low doses of the benzodiazepine. The efficacy of lamotrigine may then arise through a reduction in neuronal excitability or increased glutamate transmission, these latter a consequence of the disinhibition. Carbamazepine may also reduce excitability and glutamate release, but its broader pharmacology, manifested by sedation at higher doses complicates interpretation of its efficacy and reflects its poorer tolerability in the clinic. Valproate may be effective, at least in part, through an enhancement of GABAergic transmission. The predictive validity of the D-amphetamine/chlordiazepoxide model for efficacy in bipolar disorder remains to be established, and research with a wider range of clinically tested drugs is warranted to help validate the model further. In the meantime, the model may be useful for distinguishing novel anticonvulsant drugs with different mechanisms of action.

Animals↗
PubMed2006

Response acquisition with delayed reinforcement in a rodent model of attention-deficit/hyperactivity disorder (ADHD).

The spontaneously hypertensive rat (SHR) has been shown to exhibit behavioral characteristics analogous to those exhibited by humans diagnosed with attention-deficit/hyperactivity disorder (ADHD). The present study was conducted to further evaluate the validity of the SHR model of ADHD by characterizing learning of a novel response under conditions of delayed reinforcement. Seven experimentally naïve SHRs and a control group of seven normotensive Wistar-Kyoto (WKY) rats were exposed to a contingency where one lever press initiated pellet delivery after a 15-s, resetting delay. Rats in both groups acquired lever pressing, and the pattern of acquisition was well described with a three-parameter, sigmoidal equation. Response acquisition was retarded in the SHRs; they took longer to acquire the behavior, exhibited lower response rates and earned fewer reinforcers over the course of the experiment. When reinforcer delivery was made immediate in a subsequent condition, the SHRs exhibited higher response rates than the WKY, suggesting that the lower rates of responding seen in the SHRs were due to the reinforcer delay. The results replicate previous research on response acquisition with delayed reinforcement and provide further validation of the SHR strain as a model of ADHD. Like humans diagnosed with ADHD, the SHRs appear to be hypersensitive to delayed consequences, which in the present context, interfered with learning a novel behavior.

Animals↗
PubMed2005

A rodent model of sleep disturbances in posttraumatic stress disorder: the role of context after fear conditioning.

BACKGROUND: A prominent sleep disturbance, likely including a disruption of rapid eye movement sleep (REMS) continuity, characterizes posttraumatic stress disorder (PTSD). We set out to develop a fear conditioning paradigm in rats that displays alterations in sleep architecture analogous to those in PTSD. METHODS: Baseline polysomnographic recordings of rats were performed in a neutral context to which the rats had been habituated for several days. Rats were then shock- or mock-trained in a distinctly different context, and their sleep was studied the following day in that context. A separate group of rats was shock-trained and studied in the neutral context on the following 2 days. RESULTS: Rats that slept in the neutral context exhibited a REMS-selective increase in sleep 24 hours after training and increases in REMS and non-REMS 48 hours after training. In contrast, rats that slept in the presence of situational reminders of the training context exhibited a REMS-selective decrease in sleep 24 hours later. Animals that were mock-trained showed no changes in sleep. CONCLUSIONS: Shock training induced days-long changes in sleep architecture that were disrupted when the animal was exposed to situational reminders of the training context.

Analysis of Variance↗
PubMed2005

Rodent models of attention-deficit/hyperactivity disorder.

An ideal animal model should be similar to the disorder it models in terms of etiology, biochemistry, symptomatology, and treatment. Animal models provide several advantages over clinical research: simpler nervous systems, easily interpreted behaviors, genetic homogeneity, easily controlled environment, and a greater variety of interventions. Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder of childhood onset that is characterized by inattentiveness, hyperactivity, and impulsiveness. Its diagnosis is behaviorally based; therefore, the validation of an ADHD model must be based in behavior. An ADHD model must mimic the fundamental behavioral characteristics of ADHD (face validity), conform to a theoretical rationale for ADHD (construct validity), and predict aspects of ADHD behavior, genetics, and neurobiology previously uncharted in clinical settings (predictive validity). Spontaneously hypertensive rats (SHR) fulfill many of the validation criteria and compare well with clinical cases of ADHD. Poor performers in the five-choice serial reaction time task and Naples high-excitability rats (NHE) are useful models for attention-deficit disorder. Other animal models either focus on the less important symptom of hyperactivity and might be of limited value in ADHD research or are produced in ways that would not lead to a clinical diagnosis of ADHD in humans, even if ADHD-like behavior is displayed.

Animals↗
PubMed2004

Dysregulation of sodium channel expression in cortical neurons in a rodent model of absence epilepsy.

Due to the involvement of cortical neurons in spike-wave discharge (SWD) initiation, and the contribution of voltage-gated sodium channels (VGSCs) to neuronal firing, we examined alterations in the expression of VGSC mRNA and protein in cortical neurons in the WAG/Rij absence epileptic rat. WAG/Rij rats were compared to age-matched Wistar control rats at 2, 4, and 6 months. Continuous EEG data was recorded, and percent time in SWD was determined. Tissue from different cortical locations from WAG/Rij and Wistar rats was analyzed for VGSC mRNA (by quantitative PCR) and protein (by immunocytochemistry). SWDs increased with age in WAG/Rij rats. mRNA levels for sodium channels Nav1.1 and Nav1.6, but not Nav1.2, were found to be up-regulated selectively within the facial somatosensory cortex (at AP +0.0, ML +6.0 mm). Protein levels for Nav1.1 and Nav1.6 were up-regulated in layer II-IV cortical neurons in this region of cortex. No significant changes were seen in adjacent regions or other brain areas, including the pre-frontal and occipital cortex. In the WAG/Rij model of absence epilepsy, we identified a specific region of cortex, in layer II-IV neurons on the lateral convexity of the cortex in the facial somatosensory area, where mRNA and protein expression of sodium channel genes Nav1.1 and Nav1.6 are up-regulated. This region of cortex approximately matches the electrophysiologically determined region of seizure onset. Changes in the expression of Nav1.1 and Nav1.6 parallel age-dependent increases in seizure frequency and duration.

Action Potentials↗
PubMed2006

Enhancement of neuroprotection and heat shock protein induction by combined prostaglandin A1 and lithium in rodent models of focal ischemia.

Both prostaglandin A(1) (PGA(1)) and lithium have been reported to protect neurons against excitotoxic and ischemic injury. The present study was undertaken to examine the effects of lithium and PGA1 on heat shock proteins (HSP) and the growth arrest and DNA-damage-inducible gene (GADD153) and to evaluate if lithium could potentiate PGA(1)'s neuroprotective effects against cerebral ischemia. Rats were pretreated with a subcutaneous injection of lithium for 2 days and a single intracerebral ventricle administration of PGA(1) 15 min before ischemic insult. Brain ischemia was induced by a permanent middle cerebral artery occlusion. The infarct volume, motor behavior deficits and brain edema were analyzed 24 h after ischemic insult. The result showed that PGA(1) significantly reduced infarct volume, neurological deficits and brain edema. Except for neurological deficit, lithium enhanced PGA(1)'s neuroprotection. The neuroprotective effects of PGA(1) were associated with an up-regulation of cytoprotective heat shock proteins HSP70 and GRP78 in the ischemic brain hemisphere as determined by immunoblotting and immunofluorescence. The induction of HSP70 and GRP78 was enhanced by lithium. However, although the expression of GADD153 was enhanced significantly after pMCAO, it was not influenced by either PGA(1) or lithium or their combination. These studies suggest that lithium can potentiate PGA(1)'s neuroprotective effects and thus may have potential clinical value for the treatment of stroke in combination with other neuroprotective agents.

Analysis of Variance↗
PubMed2006

Dissociation between gene and protein expression of metabolic enzymes in a rodent model of heart failure.

Studies in advanced heart failure show down-regulation of fatty acid oxidation genes, possibly due to decreased expression of the nuclear transcription factors peroxisome proliferator activated receptor alpha (PPARalpha) and retinoid X receptor alpha (RXRalpha). We assessed mRNA and protein expression of PPARalpha and RXRalpha, and for several PPAR/RXR regulated metabolic proteins at 8 and 20 weeks following myocardial infarction induced by coronary artery ligation. Infarction resulted in heart failure, as indicated by reduced LV fractional shortening and increased end diastolic area compared to sham. There was a progressive increase in LV end systolic area, myocardial ceramide content and atrial natriuretic peptide mRNA, and a deterioration in LV fractional area of shortening from 8 to 20 weeks. Protein and mRNA expression of PPARalpha and RXRalpha were not different among groups. The mRNA for PPAR/RXR regulated genes (e.g. medium chain acyl-CoA dehydrogenase (MCAD)) was down-regulated at 8 and 20 weeks post-infarction; however, neither the protein expression nor activity of MCAD was reduced compared to sham. In conclusion, reduced mRNA expression of PPAR/RXR regulated genes is not dependent on reduced PPAR/RXR protein expression.

Acyl-CoA Dehydrogenase↗
PubMed2005

Antinociceptive activity of the selective iNOS inhibitor AR-C102222 in rodent models of inflammatory, neuropathic and post-operative pain.

Nitric oxide generated by the nitric oxide synthase (NOS) isoforms contributes to pain processing. The selective inhibition of iNOS might represent a novel, therapeutic target for the development of antinociceptive compounds. However, few isoform-selective inhibitors of NOS have been developed. The present experiments examined the anti-inflammatory and antinociceptive activity of a selective inducible nitric oxide (iNOS) inhibitor, AR-C102222, on arachidonic acid-induced ear inflammation, Freund's complete adjuvant (FCA)-induced hyperalgesia, acetic acid-induced writhing, and tactile allodynia produced by L5 spinal nerve ligation (L5 SNL) or hindpaw incision (INC). AR-C102222 at a dose of 100mg/kg p.o., significantly reduced inflammation produced by the application of arachidonic acid to the ear, attenuated FCA-induced mechanical hyperalgesia, and attenuated acetic acid-induced writhing. In the L5 SNL and INC surgical procedures, tactile allodynia produced by both procedures was significantly reduced by 30mg/kg i.p. of AR-C102222. These data demonstrate that the selective inhibition of iNOS produces antinociception in different models of pain and suggest that the iNOS-NO system plays a role in pain processing.

Animals↗
PubMed2005

Activity and expression of semicarbazide-sensitive benzylamine oxidase in a rodent model of diabetes: interactive effects with methylamine and alpha-aminoguanidine.

Previous data indicate that methylamine injection in fasted healthy mice produced a hypophagic effect dependent of neuronal K(v)1.6 channels expression and increased by alpha-aminoguanidine, an inhibitor of semicarbazide-sensitive benzylamine oxidase enzymes mainly involved in amine degradation. In the present work we have investigated: 1) the level of expression and activity of the semicarbazide-sensitive benzylamine oxidase; 2) the effect of methylamine alone and in the presence of alpha-aminoguanidine on food intake of genetic obese and type II diabetes mice (the db/db mice). Db/db mice showed higher levels of semicarbazide-sensitive benzylamine oxidase activities in adipose tissue and in plasma than their lean counterpart (db/db(+) mice). Methylamine (30-75 microg, i.c.v.) showed similar hypophagic effects in obese and lean mice consistently with the levels of neuronal K(v)1.6 found in both animal strains. Alpha-aminoguandine (50 mg/kg, i.p.) increased methylamine (i.c.v.) hypophagia in both obese and lean mice and only in obese mice when methylamine was given i.p. These results suggest a crucial role of semicarbazide-sensitive benzylamine oxidase activity in controlling methylamine hypophagia in hyperphagic diabetic mice.

Adipose Tissue↗
PubMed2006

Administration of levetiracetam after prolonged status epilepticus does not protect from mitochondrial dysfunction in a rodent model.

Neuronal death and dysfunction occur after status epilepticus (SE), and is associated with mitochondrial enzyme damage. We previously showed, using the rat perforant pathway stimulation model, that levetiracetam administration (LEV; 1000 mg/kg intraperitoneal) during established SE reduces seizure severity and prevents mitochondrial dysfunction. We now show that administration of the same dose of LEV after 5h SE, does not protect from mitochondrial dysfunction.

Animals↗
PubMed2006

Neuroprotective effects of brimonidine treatment in a rodent model of ischemic optic neuropathy.

Ischemic optic neuropathy (ION) is a common disorder caused by disruption of the arterial blood supply to the optic nerve. It can result in significant loss of visual acuity and/or visual field. An ischemic optic nerve injury was produced in rats by intravenous injection of Rose Bengal dye followed by argon green laser application to the retinal arteries overlying the optic nerve, causing a coagulopathy within the blood vessels and disruption of optic nerve and retinal perfusion. The effect of brimonidine tartrate eye drops on survival of retinal ganglion cell axons in this experimental paradigm was studied. One eye was treated and the contralateral eye served as a control. Four groups of animals were used for this study. Group 1 received 7 days of treatment with 0.15% brimonidine tartrate eye drops twice a day prior to the ischemic injury. Group 2 animals received 0.15% brimonidine tartrate eye drops twice a day for 14 days after photocoagulation injury. Animal groups 3 and 4 received eye drops of 0.9% NaCl twice a day either daily for 7 days before injury or daily for 14 days, respectively. All rats were sacrificed 5 months after the injury to ascertain long-term optic axon survival. Coagulopathy-induced optic nerve ischemia resulted in a 71% loss of optic axons. Treatment with brimonidine daily for the 7 days prior to the injury resulted in a greater survival of optic axons, with only a 56.1% loss compared to control. Brimonidine treatment every day for 14 days after the ischemic injury did not result in a significant rescue of optic axons compared to injury alone. In summary, the application of brimonidine eye drops for one week prior to an ischemic injury resulted in a statistically significant increase in survival of optic axons within the injured optic nerves. Brimonidine treatment of the eye after the ischemic injury did not result in axon rescue, and axon loss was similar to the injured optic nerves treated with saline only. These results suggest that brimonidine may have potential use for prevention of ION in at-risk patients.

Adrenergic alpha-Agonists↗