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PubMed2004

Changes of the cerebral mannitol concentrations in the course of brain death of a rodent model.

Determining the time of brain death is one of the critical issues in forensic examinations. Few authors have attempted to determine the time of brain death using pharmacokinetic approaches. We investigated cerebral concentrations of mannitol of which a single dose (1 g/kg) was administered in the course of brain death. The inflation of an epidural balloon was adopted as a rodent model of brain death. Brain death was determined using ordinary tests. Specimens were collected 4 h after brain death. Brain water content was higher in brain dead (BD) groups than those in control groups. Cerebral concentrations of mannitol in the BD group were significantly higher than those in the control group (P<0.01). In all areas of brain the concentration was the highest at the time when mannitol was administered during balloon inflation. Interhemispheric difference in the cerebrum was observed, followed by balloon inflation (P<0.05). Significant differences were observed in the average concentration of administered mannitol before and after brain death in the contralateral hemisphere (P<0.01) and in the brainstem (P<0.01). As the concentrations of mannitol in the brain are affected by cerebral trauma and brain death follows, mannitol can be used to determine the time of brain death at forensic examinations.

Animals↗
PubMedDate not supplied

Cellular delivery of human CNTF prevents motor and cognitive dysfunction in a rodent model of Huntington's disease.

The delivery of ciliary neurotrophic factor (CNTF) to the central nervous system has recently been proposed as a potential means of halting or slowing the neural degeneration associated with Huntington's disease (HD). The following set of experiments examined, in detail, the ability of human CNTF (hCNTF) to prevent the onset of behavioral dysfunction in a rodent model of HD. A DHFR-based expression vector containing the hCNTF gene was transfected into a baby hamster kidney fibroblast cell line (BHK). Using a polymeric device, encapsulated BHK-control cells and those secreting hCNTF were transplanted bilaterally into rat lateral ventricles. Eight days later, the same animals received bilateral injections of quinolinic acid (QA, 225 nmol) into the previously implanted striata. A third group received sham surgery (incision only) and served as a normal control group. Bilateral infusions of QA produced a significant loss of body weight and mortality that was prevented by prior implantation with hCNTF-secreting cells. Moreover, QA produced a marked hyperactivity, an inability to use the forelimbs to retrieve food pellets in a staircase test, increased the latency of the rats to remove adhesive stimuli from their paws, and decreased the number of steps taken in a bracing test that assessed motor rigidity. Finally, the QA-infused animals were impaired in tests of cognitive function-the Morris water maze spatial learning task, and the delayed nonmatching-to-position operant test of working memory. Prior implantation with hCNTF-secreting cells prevented the onset of all the above deficits such that implanted animals were nondistinguishable from sham-lesioned controls. At the conclusion of behavioral testing, 19 days following QA, the animals were sacrificed for neurochemical determination of striatal choline acetyltransferase (ChAT) and glutamic acid decarboxylase (GAD) levels. This analysis revealed that QA decreased striatal ChAT levels by 35% and striatal GAD levels by 45%. In contrast, hCNTF-treated animals did not exhibit any decrease in ChAT levels and only a 10% decrease in GAD levels. These results support the concepts that implants of polymer-encapsulated hCNTF-releasing cells can be used to protect striatal neurons from excitotoxic damage, produce extensive behavioral protection as a result of that neuronal sparing, and that this strategy may ultimately prove relevant for the treatment of HD.

Animals↗
PubMed1997

A kappa opioid antagonist blocks sensitization in a rodent model of Parkinson's disease.

Treatment of Parkinson's disease with levodopa is associated with fluctuations in motor function and dyskinesias, which may in part depend upon the mode of levodopa treatment. In rats with unilateral 6-hydroxydopamine lesions, intermittent levodopa results in sensitization to apomorphine-induced rotation, associated with massive ipsilateral increases in nigral dynorphin. We assessed the effects of nigral infusion of the selective kappa opioid antagonist nor-binaltorphomine (nor-BNI) in this model. Nor-BNI reduced apomorphine-induced rotation in animals receiving intermittent levodopa to a level comparable with that seen in animals treated with continuous levodopa or with saline. These data suggest that behavioural sensitization arising from intermittent levodopa therapy in a rodent model of parkinsonism depends upon increased expression of dynorphin in the striatonigral pathway and provides further insight into the mechanisms underlying motor fluctuations which develop during the treatment of Parkinson's disease.

Animals↗
PubMed1996

Long-term survival in a rodent model of disseminated brain tumors by combined intrathecal delivery of herpes vectors and ganciclovir treatment.

Brain tumors that have disseminated into cerebrospinal fluid (CSF) pathways are an unresolved therapeutic problem, especially in pediatric neurooncology. Here a gene therapy approach using the herpes simplex virus type 1 thymidine kinase (HSV-TK)/ganciclovir (GCV) paradigm was tested using an HSV vector in a rodent model of disseminated central nervous system tumors. 9L-gliosarcoma cells were implanted simultaneously into the brain and the CSF of syngeneic rats. Five days later, resulting intracerebral and leptomeningeal tumors were treated by intrathecal injection of a replication-conditional HSV vector. This vector was defective for the ribonucleotide reductase gene, but contained an intact HSV-tk gene. Systemic GCV treatment was started 2 days after vector application and continued for 14 days. Tumor-free, long-term survival (LTS) was achieved in 90% of the animals treated with this combined therapeutic approach, whereas only 30% LTS was found in animals that had received the vector alone and 10% LTS in untreated animals. This therapeutic response probably involves oncolytic, on-site replication of the vector, activation of GCV by a HSV-TK, and a strong immune response both to the vector and to 9L cells. Apparent vector-related mortality was observed in 20% of animals without subsequent GCV therapy, but no vector-related mortality was found when the animals were treated with GCV after vector application. Given the successful outcome of this experimental treatment and the apparent potential of GCV to control HSV-related toxicity, intrathecal application of HSV vectors combined with GCV treatment may be a promising approach for treatment of disseminated brain tumors.

Animals↗
PubMed2001

Nepadutant pharmacokinetics and dose-effect relationships as tachykinin NK2 receptor antagonist are altered by intestinal inflammation in rodent models.

Tachykinin NK2 receptor antagonists could reduce motility and symptoms during gastrointestinal diseases characterized by local inflammation such as diarrhea or colitis; however, how these conditions change pharmacodynamic and pharmacokinetic characteristics of NK2 receptor antagonists is unknown. We investigated the effect of the peptide NK2 receptor antagonist nepadutant on spontaneous intestinal motility or [betaAla8]NKA(4-10)-induced colonic and bladder contractions in rodent models of intestinal inflammation (enteritis induced by castor oil and rectocolitis induced by local instillation of acetic acid in rats, enteritis induced by bacterial toxins in mice). In the castor oil model, the oral/intraduodenal bioavailability of nepadutant was also determined. The intrarectal (i.r.) administration of nepadutant (100 nmol/kg) did not reduce [betaAla8]NKA(4-10) (10 nmol/kg i.v.)-induced colonic and bladder contractions in normal animals, but the same dose of nepadutant produced an inhibitory effect in the two organs following rectocolitis; in contrast, nepadutant is equieffective by the intravenous route in normal and colitic animals. In this model, nepadutant (100 nmol/kg i.r. or i.v.) decreased spontaneous colonic hypermotility, without affecting motility in controls. The intraduodenal administration of nepadutant (30 nmol/kg), which was ineffective on [betaAla8]NKA(4-10) (10 nmol/kg i.v.)-induced colonic and bladder contractions in control animals, abolished bladder contractions in castor oil-pretreated animals. In this latter group, the oral and intraduodenal bioavailability of nepadutant showed a 7- to 9-fold increase with respect to controls. Oral administration of nepadutant, in nanomolar or subnanomolar dosage, reduced diarrhea induced by bacterial toxins in mice. It is concluded that intestinal inflammation increases nepadutant absorption in the intestine, enhancing its activity. These results suggest that a drug with a limited oral bioavailability could be used for treating gastrointestinal diseases associated with a local inflammation.

Acetates↗
PubMed2006

Drug discovery in dementia: the role of rodent models.

Recent advances in the understanding of the pathophysiological mechanisms underlying Alzheimer's disease have pointed to novel strategies for drug development. Animal models have contributed considerably to these advances, and will have a key role in the evaluation of therapeutics that could have the potential not just to alleviate the dementia associated with Alzheimer's disease, but to modify the disease process. Here, we summarize and critically evaluate current rodent models of dementia, and discuss their role in drug discovery and development.

Alzheimer Disease↗
PubMed2004

N-acetylcysteine attenuates lung injury in a rodent model of fracture.

BACKGROUND: Neutrophil-mediated lung injury is a cause of significant morbidity and mortality in patients with multiple injuries. We have shown previously that fracture hematoma can activate neutrophils and is thus a putative mediator of the systemic inflammatory response syndrome (SIRS), acute respiratory distress syndrome (ARDS) and multiple organ failure (MOF) in those patients with severe skeletal trauma. Our aim was to establish a rodent model of fracture which caused lung injury and subsequently to administer a drug following fracture to attenuate the lung injury. The drug we chose was N-acetylcysteine, a potent antioxidant. ANIMALS AND METHODS: Adult Sprague-Dawley rats were assigned to 4 groups: (1) general anesthetic only, (2) general anesthetic with bilateral femur fractures and nailing, (3) general anesthetic and N-acetylcysteine, (4) general anesthetic with bilateral femur fractures and nailing and N-acetylcysteine after the injury (n = 6 in each group). The dose of N-acetylcysteine was 0.5 mg/kg which was given intraperitoneally after injury to the treated groups. The rats were killed 24 hours after injury and some parameters of lung injury were evaluated--i.e., bronchoalveolar lavage (BAL), lung tissue myeloperoxidase levels (MPO) and wet/dry ratios of lung tissue. The results were analyzed, using one-way analysis of variance. RESULTS: Bilateral femur fracture produced a significant lung injury, measured by increases in MPO (25-43 microg/g tissue) and BAL protein (460-605 microg/mL). This effect was attenuated by treatment with N-acetylcysteine (MPO 43-9 microg/mL, BAL protein 605-198 microg/mL). INTERPRETATION: N-acetyl cysteine, if given after skeletal trauma, is of potential therapeutic benefit, in preventing SIRS, ARDS and MOF.

Acetylcysteine↗
PubMed2006

Effects of isoarecolone, a nicotinic receptor agonist in rodent models of nicotine dependence.

RATIONALE: The nicotinic receptor agonist, isoarecolone, has 'nicotine-like' subjective properties as detected by rats in a discrimination paradigm. However, isoarecolone lacks the intra-accumbens dopamine-releasing effects, a feature akin to most abused substances. In the five-choice serial reaction time task, isoarecolone can enhance attention and thus may be developed as a cognitive enhancer. OBJECTIVE: The present experiments assess the dependence profile of isoarecolone in rodent models of nicotine dependence. METHOD AND RESULTS: Tests for cross-substitution in which isoarecolone is substituted for nicotine [0.3 mg/kg/infusion (inf)] self-administration suggest isoarecolone to have nominal reinforcing properties (0.3 or 1.0 mg/kg/inf); intake of isoarecolone declined over three test sessions in which responding was no different from saline extinction, and behaviour was reinstated by re-presenting nicotine. In a model of nicotine-seeking behaviour, rats having been extinguished by removal of nicotine (0.03 mg/kg/inf) and associated cues, the presentation of priming doses of nicotine (0.1-0.4 mg/kg s.c.) with the cues robustly reinstated responding of nicotine-seeking behaviour. Tests with priming doses of isoarecolone (1-20 mg/kg s.c.) shown previously to generalise to nicotine in discrimination tests produced significant levels of reinstatement but the responses were significantly less compared to nicotine-induced reinstatement. CONCLUSION: Overall, these results suggest that isoarecolone with its unique profile of behavioural activity should be further examined for treating chronic diseases that are characterised by attentional dysfunction.

Animals↗
PubMed1997

Influence of ischemia and reperfusion on the course of brain tissue swelling and blood-brain barrier permeability in a rodent model of transient focal cerebral ischemia.

Brain swelling is a serious complication associated with focal ischemia in stroke and severe head injury. Experimentally, reperfusion following focal cerebral ischemia exacerbates the level of brain swelling. In this study, the permeability of the blood-brain barrier has been investigated as a possible cause of reperfusion-related acute brain swelling. Blood-brain barrier disruption was investigated using Evans Blue dye and [14C]aminoisobutyric acid autoradiography in a rodent model of reversible middle cerebral artery (MCA) occlusion. Acute brain swelling and cerebral blood flow (CBF) during ischemia and reperfusion were analyzed from double-label CBF autoradiograms after application of the potent vasoconstrictor peptide endothelin-1 to the MCA. Ischemia was apparent within ipsilateral MCA territory, 5 min after endothelin-1 application to the exposed artery. Reperfusion, examined at 30 min and 1, 2, and 4 h, was gradual but incomplete within this time frame in the core of middle cerebral artery territory and associated with significant brain swelling. Ipsilateral hemispheric swelling increased over time to a maximum (>5%) at 1-2 h after endothelin-1 but was not associated with a significant increase in the ipsilateral transfer constant for [14C]aminoisobutyric acid over this time frame. These results indicate that endothelin-1 induced focal cerebral ischemia is associated with an acute but reversible hemispheric swelling during the early phase of reperfusion which is not associated with a disruption of the blood-brain barrier.

Aminoisobutyric Acids↗
PubMed2005

MK801 and amantadine exert different effects on subthalamic neuronal activity in a rodent model of Parkinson's disease.

Efforts to develop adjuvant therapies for the treatment of Parkinson's disease (PD) have led to interest in drugs that could mimic the therapeutic effects of lesion or deep brain stimulation of the subthalamic nucleus (STN). Extracellular single unit recordings were conducted to determine whether noncompetitive NMDA receptor blockade, suggested to have potential as an adjuvant treatment in PD, attenuates rate increases and firing pattern changes observed in the STN in a rodent model of PD. Systemic administration of the noncompetitive NMDA antagonist MK801 to rats with unilateral dopamine cell lesions did not significantly alter burstiness or interspike interval coefficient of variation, although mean firing rate decreased by a modest 20% with 50% of neurons showing decreases in rate >15% and spike train power in the 3-8-Hz (theta) range was reduced. MK801, combined with the D1 dopamine agonist SKF 38393 in intact rats or administered alone in lesioned rats, also significantly reduced incidence of multisecond (2-60 s) periodic oscillatory activity. Amantadine, a drug currently used as an adjuvant agent in PD whose beneficial effects are commonly attributed to its noncompetitive NMDA antagonist properties, had effects that contrasted with those of MK801. In both intact and lesioned animals, amantadine significantly increased STN firing rates and total spike train power in the 8-50-Hz range and did not alter spike power in the 3-8-Hz range or multisecond oscillatory activity. These observations show that an effective noncompetitive NMDA antagonist such as MK801 induces modest change in STN activity in 6-hydroxydopamine (6-OHDA)-lesioned rats, with the most notable effect on multisecond periodicities in firing rate and theta frequency total spike power. Amantadine's effects differed from MK801's, raising questions about its primary mechanism of action and the role in PD pharmacotherapy of the STN rate increases induced by this drug.

Action Potentials↗
PubMed2005

Multidose risperidone treatment evaluated in a rodent model of tardive dyskinesia.

Risperidone is a second-generation antipsychotic that lacks acute motor side effects at low doses (<6 mg/day), but above this level is associated with parkinsonism and akathesia. The literature suggests an association between acute motor side effects and tardive dyskinesia (TD); therefore, we hypothesized that low dose levels of risperidone will spare TD. As clinical studies of TD liability with fixed doses of risperidone are difficult to conduct, we tested low and high doses of risperidone in a rodent model of TD, vacuous chewing movements (VCMs) production. Low doses of risperidone (1.5 mg/kg/day) resulted in control levels of VCMs after 6 months of treatment, whereas high doses of risperidone (6 mg/kg/day) produced VCM in the same range as haloperidol. Plasma drug levels are reported. If this animal model predicts TD risk in humans, the TD liability with low-dose risperidone is at a placebo level, whereas higher doses show haloperidol-like TD risk, as predicted from the acute motor effects.

Animals↗
PubMed2003

An assessment of the effects of serotonin 6 (5-HT6) receptor antagonists in rodent models of learning.

Antagonists of serotonin 6 (5-HT6) receptors have been reported to enhance cognition in animal models of learning, although this finding has not been universal. We have assessed the therapeutic potential of the specific 5-HT6 receptor antagonists 4-amino-N-(2,6-bis-methylamino-pyrimidin-4-yl)-benzenesulfonamide (Ro 04-6790) and 5-chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfonamide (SB-271046) in rodent models of cognitive function. Although mice express the 5-HT6 receptor and the function of this receptor has been investigated in mice, all reports of activity with 5-HT6 receptor antagonists have used rat models. In the present study, receptor binding revealed that the pharmacological properties of the mouse receptor are different from the rat and human receptor: Ro 04-6790 does not bind to the mouse 5-HT6 receptor, so all in vivo testing included in the present report was conducted in rats. We replicated previous reports that 5-HT6 receptor antagonists produce a stretching syndrome previously shown to be mediated through cholinergic mechanisms, but Ro 04-6790 and SB-271046 failed to attenuate scopolamine-induced deficits in a test of contextual fear conditioning. We also failed to replicate the significant effects reported previously in both an autoshaping task and in a version of the Morris water maze. The results of our experiments are not consistent with previous reports that suggested that 5-HT6 antagonists might have therapeutic potential for cognitive disorders.

Animals↗
PubMed2004

Apoptosis in a rodent model of cranial suture fusion: in situ imaging and gene expression analysis.

Craniosynostosis, the premature fusion of cranial sutures, is one of the most common craniofacial anomalies, with a reported incidence of up to one in 2500 live births. Despite its prevalence, the cause of craniosynostosis remains unknown. Previously, apoptosis has been postulated to be a contributing factor in the pathogenesis of craniosynostosis, although the role of programmed cell death in cranial sutures is poorly understood. To address this problem, the authors used an established rodent model of posterior-frontal suture fusion and sagittal suture patency to globally examine apoptosis in cranial sutures. Apoptosis was evaluated by systemically coinjecting Sprague-Dawley rats with both fluorescent and technetium-99m-labeled annexin V at time points before, during, and after the period of predicted posterior-frontal suture fusion to determine the magnitude and time course of overall apoptotic activity in both fusing and patent sutures. Using these novel in situ imaging techniques, the authors observed a significant increase in the overall levels of apoptosis in both the posterior-frontal and sagittal suture complexes during the period of predicted posterior-frontal suture fusion. To further explore this increase in apoptotic activity, they used microarray technology to study apoptosis-related genes within the suture complex. Interestingly, there was activation of distinct apoptotic pathways in the posterior-frontal and sagittal sutures during the period of predicted posterior-frontal suture fusion. Whereas increased transcription of genes associated with the mitochondria-mediated apoptotic pathway occurred in the posterior-frontal suture during fusion, activation of genes associated with the death receptor-mediated apoptotic pathway predominated in the patent sagittal suture during the same time period. These data suggest that although overall apoptotic activity in rat patent and fusing sutures is similar, the pathways mediating apoptosis within each suture are distinct.

Animals↗
PubMed2005

Adolescent vulnerabilities to chronic alcohol or nicotine exposure: findings from rodent models.

This article presents an overview of the proceedings from a symposium entitled "Is adolescence special? Possible age-related vulnerabilities to chronic alcohol or nicotine exposure," organized by Susan Barron and Linda Spear and held at the 2004 Research Society on Alcoholism Meeting in Vancouver, British Columbia. This symposium, co-sponsored by the Fetal Alcohol Syndrome Study Group and the Neurobehavioral Teratology Society, focused on our current knowledge regarding the long-term consequences of ethanol and/or nicotine exposure during adolescence with the emphasis on data from rodent models. The support from these two societies represents the understanding by these research groups that adolescence represents a unique developmental stage for the effects of chronic drug exposure and also marks an age in which many risky behaviors including alcohol consumption and smoking typically begin. The speakers included (1) Aaron White, who presented data on the effects of adolescent ethanol exposure on subsequent motor or cognitive response to an ethanol challenge in adulthood; (2) Richard Bell, who presented data suggesting that genetic differences could play a role in adolescent vulnerability to ethanol; (3) Craig Slawecki, who presented data looking at the effects of chronic exposure to alcohol or nicotine on neurophysiologic and behavioral end points; and (4) Ed Levin, who presented data on acute and long-term consequences of adolescent nicotine exposure. Finally, Linda Spear provided some summary points and recommendations regarding unresolved issues and future directions.

Adolescent↗
PubMed1991

Diurnal rhythm of core body temperature is phase advanced in a rodent model of depression.

We examined the diurnal rhythm of core body temperature in a strain of rats with an upregulated central muscarinic receptor system. The Flinders-Sensitive Line (FSL) was derived by selectively breeding rats for sensitivity to cholinergic agonists. When compared to control rats, the FSL rats showed a remarkably strong phase advance of the acrophase in body temperature during a standard light-dark schedule. Some patients with some types of depression also show phase advances in a number of circadian rhythms, including temperature. Our finding of a phase advance in a rodent model with a known upregulated muscarinic receptor system is compatible with both the phase advance and the muscarinic overdrive theories of depression. These findings also further validate the usefulness of the FSL rats in the study of depression.

Animals↗
PubMed1979

The effects of transient candidemia on the brain: preliminary observations on a rodent model for experimental deep candidosis.

Deep candidosis was established in healthy uncompromised Wistar rats by injecting Candida albicans into the right internal carotid artery. Death of these animals could be produced within seven days by injecting 10(7) yeasts. The kidneys were most severely infected, and the entire brain was involved. No animal demonstrated leptomeningitis. Within one to two days microabscesses developed, subsiding into a histiocytic response in five to seven days. By seven days, chronic inflammation with noncaseating granulomas was seen. Throughout the study, cerebrospinal fluid and blood cultures failed to demonstrate the fungus. This rodent model is similar to human cerebral candidosis.

Animals↗
PubMed2005

LY503430: pharmacology, pharmacokinetics, and effects in rodent models of Parkinson's disease.

Glutamate is the major excitatory transmitter in the brain. Recent developments in the molecular biology and pharmacology of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-subtype of glutamate receptors have led to the discovery of selective, potent and systemically active AMPA receptor potentiators. These molecules enhance synaptic transmission and play important roles in plasticity and cognitive processes. In the present studies we characterized a novel AMPA receptor potentiator, LY503430, on recombinant human GLU(A1-4) and native preparations in vitro, and then evaluated the potential neuroprotective effects of the molecule in rodent models of Parkinson's disease. Results indicated that at submicromolar concentrations LY503430 selectively enhanced glutamate-induced calcium influx into HEK293 cells transfected with human GLU(A1), GLU(A2), GLU(A3), or GLU(A4) AMPA receptors. The molecule also potentiated AMPA-mediated responses in native cortical, hippocampal and substantia nigra neurones. LY503430 had good oral bioavailability in both rats and dogs. We also report here that LY503430 provided dose-dependent functional and histological protection in animal models of Parkinson's disease. The neurotoxicity following unilateral infusion of 6-hyrdoxydopamine (6-OHDA) into either the substantia nigra or the striatum of rats and that following systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice were reduced. Interestingly, LY503430 also had neurotrophic actions on functional and histological outcomes when treatment was delayed until well after (6 or 14 days) the lesion was established. LY503430 also produced some increase in brain derived neurotrophic factor (BDNF) in the substantia nigra and a dose-dependent increase in growth associated protein-43 (GAP-43) expression in the striatum. Therefore, we propose that AMPA receptor potentiators such as LY503430 offer the potential of a new disease modifying therapy for Parkinson's disease.

Amides↗
PubMed2004

Neurotrophic actions of the novel AMPA receptor potentiator, LY404187, in rodent models of Parkinson's disease.

Recent developments in the molecular biology and pharmacology of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors has led to the discovery of selective, potent and systemically active AMPA receptor potentiators. These molecules enhance synaptic transmission and evidence suggests that they play important roles in plasticity and cognitive processes. Activation of AMPA receptors also increases neuronal activation and activity-dependent signalling, which may increase brain-derived neurotrophic factor (BDNF) expression and enhance cell proliferation in the brain. We therefore hypothesised that an AMPA receptor potentiator may provide neurotrophic effects in rodent models of Parkinson's disease. In the present studies we report that the potent and selective AMPA receptor potentiator, R,S-N-2-(4-(4-Cyanophenyl)phenyl)propyl 2-propanesulfonamide (LY404187), provides both functional, neurochemical and histological protection against unilateral infusion of 6-hydroxydopamine into the substantia nigra or striatum of rats. The compound also reduced 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity in mice. Interestingly, we were also able to observe large functional and histological effects when we delayed treatment until after cell death had occurred (3 or 6 days after 6-hydroxydopamine infusion), supporting a neurotrophic mechanism of action. In addition, LY404187 provided a dose-dependent increase in growth-associated protein-43 expression in the striatum. Therefore, we propose that AMPA receptor potentiators offer the potential of a new therapy to halt the progression and perhaps repair the degeneration in Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗