Biomedical subjects

Timothy Schallert

Publications and source records attributed to Timothy Schallert.

At least 19 recordsLinked to original sources

PubMed2006

Protease-activated receptor-1 mediates protection elicited by thrombin preconditioning in a rat 6-hydroxydopamine model of Parkinson's disease.

The etiology of Parkinson's disease remains poorly understood, and current treatment options do not slow disease progression. Recently, chemical (thrombin) preconditioning (TPC) was found to be protective in a 6-hydroxydopamine (6-OHDA) model of the disease. It is important to understand the mechanisms behind these thrombin-induced protective effects. The current study was conducted in the rat to determine whether the protective effects of TPC are mediated via activation of protease-activated receptors (PARs). Preconditioning with specific local infusion of agonist peptides for PAR-1 and PAR-4 3 days before unilateral 6-OHDA administration (10 microg into the medial forebrain bundle) was tested. In addition, co-administration of a PAR-1 antagonist with TPC was examined. In a neurobehavioral assessment battery, PAR-1 agonist preconditioning provided protection in a vibrissae-elicited forelimb placing test, a forelimb-use asymmetry test, and a corner turn test. In addition, inclusion of a PAR-1 antagonist prevented the protective effects elicited by TPC. In contrast to the effects of the PAR-1 agonist, PAR-4 agonist preconditioning afforded no such protection. Indeed, in a lower-dose model of 6-OHDA (5 microg), PAR-4 preconditioning significantly increased behavioral deficits. These results indicate that the protective effects of TPC in this model are mediated through PAR-1 activation. Neither the effects of PAR-1 nor TPC on later 6-OHDA-induced behavioral deficits appeared to be mediated through (DA) content sparing. Further mechanistic studies on the actions of PAR-1 and PAR-4 as detrimental in experimental models of Parkinson's disease are warranted.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2006

Olfactory discrimination deficits in mice lacking the dopamine transporter or the D2 dopamine receptor.

Previous pharmacological studies have implicated dopamine as a modulator of olfactory bulb processing. Several disorders characterized by altered dopamine homeostasis in olfaction-related brain regions display olfactory deficits. To further characterize the role of dopamine in olfactory processing, we subjected dopamine transporter knockout mice (DAT -/-) and dopamine receptor 2 knockout mice (D2 -/-) to a battery of olfactory tests. In addition to behavioral characterization, several neurochemical markers of olfactory bulb integrity and function were examined. DAT -/- mice displayed an olfactory discrimination deficit, but did not differ detectably from DAT wildtype (DAT +/+) mice in odor habituation, olfactory sensitivity, or odor recognition memory. Neurochemically, DAT -/- mice have decreased D2 receptor staining in the periglomerular layer of the olfactory bulb and increased tyrosine hydroxylase immunoreactivity compared to DAT +/+ controls. D2 -/- mice exhibited the same olfactory deficit as the DAT -/- mice, further supporting the role of dopamine at the D2 synapse in olfactory discrimination processing. The findings presented in this paper reinforce the functional significance of dopamine and more specifically the D2 receptor in olfactory discrimination and may help explain the behavioral phenotype in the DAT and D2 knockout mice.

Animals↗

PubMed2006

Persistent neurochemical and behavioral abnormalities in adulthood despite early iron supplementation for perinatal iron deficiency anemia in rats.

BACKGROUND: Iron deficiency anemia (IDA) has been associated with altered cognitive, motor, and social-emotional outcomes in human infants. We recently reported that rats with chronic perinatal IDA, had altered regional brain iron, monoamines, and sensorimotor skill emergence during early development. OBJECTIVE: To examine the long-term consequences of chronic perinatal IDA on behavior, brain iron and monoamine systems after dietary iron treatment in rats. METHODS: Sixty dams were randomly assigned to iron-sufficient (CN) or low-iron (EID) diets during gestation and lactation. Thereafter, all offspring were fed the iron-sufficient diet, assessed for hematology and behavior after weaning and into adulthood and for brain measures as adults (regional brain iron, monoamines, dopamine and serotonin transporters, and dopamine receptor). Behavioral assessments included sensorimotor function, general activity, response to novelty, spatial alternation, and spatial water maze performance. RESULTS: Hematology and growth were similar for EID and CN rats by postnatal day 35. In adulthood, EID thalamic iron content was lower. Monoamines, dopamine transporter, and dopamine receptor concentrations did not differ from CN. EID serotonin transporter concentration was reduced in striatum and related regions. EID rats had persisting sensorimotor deficits (delayed vibrissae-evoked forelimb placing, longer sticker removal time, and more imperfect grooming chains), were more hesitant in novel settings, and had poorer spatial water maze performance than CN. General activity and spatial alternation were similar for EID and CN. CONCLUSION: Rats that had chronic perinatal IDA showed behavioral impairments that suggest persistent striatal dopamine and hippocampal dysfunction despite normalization of hematology, growth and most brain measures.

Anemia, Iron-Deficiency↗

PubMed2006

Local fluorouracil chemotherapy interferes with neural and behavioral recovery after brain tumor-like mass compression.

In this study, we investigated the impact of intracerebral delivery of chemotherapy on functional recovery from focal cortical tissue displacement, characteristic of brain tumors. Unilateral focal brain compression was induced by epidural implantation of an inverted hemisphere-shaped bead over the sensorimotor cortex. Microinjections of a total of 1mg chemoagent fluorouracil or the same volume of saline were made into the compressed cortex. Behavioral tests of forelimb sensorimotor function were conducted during 4 weeks' observation. Rats subjected to any of the three types of lesions, saline microinjection plus cortical compression, chemoagent microinjection alone, or chemoagent microinjection combined with cortical compression, demonstrated significant behavioral deficits in several sensorimotor tasks, compared with saline-microinjected control animals. In placing tests, behavioral deficits elicited by each single treatment were worsened by combined treatment with chemoagent microinjection and focal cortical compression. Concurrently, local delivery of chemoagent into the compressed cortex induced increased cortical tissue loss, necrosis and apoptosis. These data indicate that local chemotherapy exacerbates compression-induced neurological impairment, and a model of controlled focal cortical compression may provide a valuable means to improve anti-cancer therapeutic designs with reduced deterioration of brain function.

Animals↗

PubMed2006

Interruption of functional recovery by the NMDA glutamate antagonist MK801 after compression of the sensorimotor cortex: implications for treatment of tumors or other mass-related brain injuries.

Glutamate antagonists have recently been shown to limit tumor growth, providing potential new therapeutic targets and strategies against brain tumors. Here, we demonstrate that the glutamate NMDA receptor antagonist MK801, after a delay, adversely reverses functional recovery in rats with compressive mass lesions of the sensorimotor cortex. Our data suggest that the controlled focal cortical compression model may be a valuable pre-clinical tool to screen compounds for the treatment of brain tumors. It may be possible to use this model to develop interventions that maintain anti-cancer effects but with diminished harm to bystander tissue and brain plasticity.

Animals↗

PubMed2006

A simple modification of the water maze test to enhance daily detection of spatial memory in rats and mice.

The water maze is one of the most frequently used tools in behavioral neuroscience. Many variations of the water maze task have been used; however, established water maze protocols have several disadvantages. Notably, these protocols demand considerable time to perform reference and probe tests separately. Here, we suggest a modified protocol, which is rapidly performed, is sensitive to cognitive deficits, and can assay reference as well as strategy-switching ability. The platform is relocated randomly within the target quadrant with each training trial. Because the rodents must spend more time searching within the target quadrant, every trial effectively becomes a probe trial. The rodents are then run in the switching strategy test, where the platform is randomly placed along the wall of the pool. The best new strategy would thus be to search along the walls of the pool systematically. The percent distance traveled and time spent near the wall is evaluated across trials, as is the distance traveled and time spent in the previously correct quadrant. In this way one can assess whether the rodent is continuing to search in the older platform location (i.e., displaying a strategy-switching problem) or whether it has successfully adopted a new search strategy.

Animals↗

PubMed2006

Behavioral tests for preclinical intervention assessment.

Select functional outcome tests commonly used for evaluating sensorimotor and cognitive capacity in rodents with focal intracerebral ischemic or hemorrhagic injury are described, along with upgrades and issues of concern for translational research. An emphasis is placed on careful quantitative and qualitative assessment of acute and long-term behavioral deficits, and on avoidance of frequent pitfalls. Methods for detecting different degrees of injury and treatment-related improvements are included. Determining the true potential of an intervention requires a set of behavioral analyses that can monitor compensatory learning. In a number of preclinical outcome tests, animals can develop remarkably effective "tricks" that are difficult to detect but frequently lead to dramatic improvements in performance, particularly with repeated practice. However, some interventions may facilitate learning without promoting brain repair, but these may not translate into a meaningful level of benefit in the clinic. Additionally, it is important to determine whether there are any preinjury functional asymmetries in order to accurately assess damage-related changes in behavior. This is illustrated by the fact that some animals have chronic endogenous asymmetries and that others, albeit infrequently, can sustain a spontaneous cerebral stroke, without any experimental induction, that can lead to chronic deficits as reflected by behavioral, imaging, and histological analyses. Finally, a useful new modification of the water maze that involves moving the platform from trial to trial within the target quadrant is reviewed, and its advantages over the standard version are discussed.

Animals↗

PubMed2006

Mass-related traumatic tissue displacement and behavior: a screen for treatments that reduce [corrected] harm to bystander cells and recovery of function.

In this study, we focused on a preclinical model of brain compression injury that has relevance to pathological conditions such as tumor, hematoma, blood clot, and intracerebral bony fragment. We investigated behavioral impairment as a result of rapid-onset small mass, and the factors involved in lesion formation and neuroplasticity. An epidural bead implantation method was adopted. Two sizes (1.5 mm and 2.0 mm thick) of hemisphere-shaped beads were used. The beads were implanted into various locations over the sensorimotor cortex (SMC--anterior, middle and posterior). The effects of early versus delayed bead removal were examined to model clinical neurosurgical or other treatment procedures. Forelimb and hind-limb behavioral deficits and recovery were observed, and histological changes were quantified to determine brain reaction to focal compression. Our results showed that the behavioral deficits of compression were influenced by the location, timing of compression release, and magnitude of compression. Even persistent compression by the thicker bead (2.0 mm) caused only minor behavioral deficits, followed by fast recovery within a week in most animals, suggesting a mild lesion pattern for this model. Brain tissue was compressed into a deformed shape under pressure with slight tissue damage, evidenced by pathological evaluation on hematoxylin and eosin (H&E)- and TUNEL-stained sections. Detectable but not severe behavioral dysfunction exhibited by this model makes it particularly suitable for direct assessment of adverse effects of interventions on neuroplasticity after brain compression injury. This model may permit development of treatment strategies to alleviate brain mass effects, without disrupting neuroplasticity.

Animals↗

PubMed2006

Long-lasting neural and behavioral effects of iron deficiency in infancy.

Infants are at high risk for iron deficiency and iron-deficiency anemia. This review summarizes evidence of long-term effects of iron deficiency in infancy. Follow-up studies from preschool age to adolescence report poorer cognitive, motor, and social-emotional function, as well as persisting neurophysiologic differences. Research in animal models points to mechanisms for such long-lasting effects. Potential mechanisms relate to effects of iron deficiency during brain development on neurometabolism, myelination, and neurotransmitter function.

Anemia, Iron-Deficiency↗

PubMed2006

Long-term effects of experimental intracerebral hemorrhage: the role of iron.

OBJECT: Intracerebral hemorrhage (ICH) causes brain atrophy and neurological deficits. The mechanisms of brain atrophy after ICH are poorly understood, although recent evidence suggests that some ICH-induced brain injury results from the products of hemoglobin degradation, including iron. In this study the authors examine the role of iron in brain atrophy and neurological deficits following ICH. METHODS: Male Sprague-Dawley rats received an infusion of either 100 microl autologous whole blood or saline into the right caudate. Hematoxylin and eosin staining was used for histological examination, and iron levels and ferritin immunoreactivities were also examined. Deferoxamine was used as an iron chelator. Over the duration of the experiment, the rats underwent behavioral testing (forelimb placing, forelimb use asymmetry, and corner turn tests). Brain atrophy in the caudate with prolonged neurological deficits occurred after ICH. Although partial functional recovery occurred with time, residual neurological deficits were still detectable at 3 months postprocedure. Iron accumulation and ferritin upregulation were present in the ipsilateral caudate. Deferoxamine reduced brain atrophy and improved behavioral outcomes, and it also reduced brain ferritin immunoreactivity. CONCLUSIONS: An ICH results in an accumulation of iron in the brain that is not cleared within 3 months and that contributes to brain tissue loss and neurological deficits posthemorrhage. Iron chelation may be a useful therapy for patients with ICH.

Animals↗

PubMed2005

Behavioral and histological effects of chronic antipsychotic and antidepressant drug treatment in aged rats with focal ischemic brain injury.

Psychotropic drugs are commonly used in the elderly, including those who may sustain ischemic attacks. Concomitant CNS medication may interfere with functional recovery. The present study evaluated the effect of risperidone, an atypical neuroleptic, and fluoxetine, a selective serotonin reuptake inhibitor, on histological and functional outcome after experimental stroke in aged rats, which might be more vulnerable to brain insults. Aged Wistar rats were treated with risperidone at a dose of 1 mg/kg (i.p., once a day), fluoxetine at a dose of 5 mg/kg (i.p., once a day), or their combination. Drug treatment was started 7 days before focal cortical photothrombosis (Rose Bengal, 20 mg/kg) and continued for 28 days thereafter. Sensorimotor recovery was assessed by a new beam-walking test and spatial learning by the Morris water-maze before cortical stroke, immediately after stroke, and at the end of follow-up. Infarct volumes were measured from nitroblue tetrazolium-stained sections at the end of follow-up. The high slip ratio for the contralateral hindlimb in ischemic rats treated with risperidone indicated sensorimotor impairment when tested 2 h after drug administration. Sensorimotor impairment was not observed, however, when the rats were tested 24 h after risperidone administration. Similarly, water-maze performance was impaired 2 h after risperidone. Fluoxetine did not affect sensorimotor or water-maze performance. Cortical infarct volumes were not different in ischemic controls and ischemic rats treated with antipsychotic drugs. The present study showed that an atypical neuroleptic, risperidone, acutely impairs behavioral performance, but does not affect histological or functional outcome in aged rats subjected to cortical photothrombosis.

Affect↗

PubMed2005

Long-term effects of sequential cortical infarcts on scar size, brain volume and cognitive function.

Focal ischemia induces long-term pathophysiological consequences in widespread brain areas. Here we analyzed long-term effects of sequential cortical lesions on brain volume and cognitive function. Rats received either single photothrombotic lesions in the forelimb sensorimotor cortex (SL) or two lesions in sequence either immediately (DL0), 2 days (DL2), 7 days (DL7), or 10 days (DL10) after the first surgery in the homotopic contralateral area. Infarct and global brain volume were measured 7 days (SL and DL2 groups) and one month (all groups) after the last period of ischemia. In the weeks following a stroke, the single lesion shrank considerably. This shrinkage was accentuated by a further lesion received either earlier or later. Thirty-one days after obtaining the second lesion, the lesion scars on both sides had a mean volume of 5.8 +/- 2.3 mm3 in DL2 as compared to 8.5 +/- 3.5 mm3 in SL-animals. In addition, there was a super-additive loss of residual brain volume by 2.2-8.0% in each hemisphere in animals with sequential lesions. In the watermaze, this loss of brain volume corresponded to a slight but significant impairment in performance. The present study revealed a complex interaction of lesions in animals with sequential strokes associated with global reduction of brain volume and cognitive impairment indicating degenerative processes beyond the lesions itself.

Animals↗

PubMed2005

Intracerebral hemorrhage in the iron-deficient rat.

BACKGROUND AND PURPOSE: Iron contributes to brain injury after intracerebral hemorrhage (ICH). Because ICH may occur in the context of iron deficiency anemia (IDA), a common nutritional disorder, the purpose of this study was to determine whether IDA in rats affects brain edema, functional behavior, and changes in brain iron-handling proteins after ICH. METHODS: Six-week-old male rats (n=75) were randomized to non-IDA or IDA groups and provided iron-sufficient or -deficient diets, respectively. After 1 month, 100 microL autologous blood was infused into the right basal ganglia (BG). Brains removed at days 1, 3, 7, and 28 after ICH were assessed for regional brain water content and BG transferrin and transferrin receptor concentrations (Western blotting). Sensorimotor measures of functional recovery were assessed. RESULTS: Brain water content was increased for IDA versus non-IDA in injured cortex and BG at day 3 (P<0.05). IDA rats had impaired left forepaw placing and more asymmetric forelimb use versus non-IDA after ICH (P<0.05). Transferrin and transferrin receptor concentrations in the BG were increased for IDA versus non-IDA within the first week (P<0.05). CONCLUSIONS: Rats with IDA have greater brain edema, poorer sensorimotor outcome, and a greater expression of iron regulatory proteins than non-IDA rats after ICH, suggesting brain iron status is a determinant of injury severity and recovery.

Anemia, Iron-Deficiency↗

PubMed2005

An intermittent, controlled-rate, slow progressive degeneration model of Parkinson's disease: antiparkinson effects of Sinemet and protective effects of methylphenidate.

The causes of nigrostriatal neuron degeneration in Parkinson's disease (PD) are not known, but it has been suggested that exogenous or endogenous factors or neurotoxins may play a role. The degree of vulnerability to neurotoxins or other potential mediators of nigral dopamine cell death is thought to be important in understanding Parkinson's disease. In most animal models, the rate of terminal degeneration and corresponding functional impairment is too rapid to investigate effectively either cell vulnerability or the potential benefits of some neuroprotective treatments. In the present study, a new model of Parkinson's disease is described that might help in addressing the issue of nigral cell vulnerability and to evaluate interventions with clinical potential. 6-Hydroxydopamine (6-OHDA) was infused in escalating, intrastriatal doses over several weeks. Control animals received multiple infusions of vehicle at the same volume. Behavioral testing was carried out between each infusion, including forelimb-use and somatosensory function. A symptomatic threshold was established for each animal, indicating the amount of neurotoxin required to induce a stable deficit. Oral administration of L-DOPA (Sinemet) ameliorated limb-use asymmetries acutely. An immunocytochemical assay for tyrosine hydroxylase, a dopamine cell marker, revealed a partial loss of immunoreactive cells in the substantia nigra. Animals that were co-administered methylphenidate (MPH), a dopamine transport inhibitor, along with the 6-OHDA were spared from the behavioral and neurochemical effects of 6-OHDA, despite receiving more than twice as much neurotoxin as controls. These data suggest that establishing a symptomatic threshold preclinically may help researchers evaluate potential treatments and model individual and group resistance to nigrostriatal insults.

Animals↗

PubMed2005

Behavioral effects of photothrombotic ischemic cortical injury in aged rats treated with the sedative-hypnotic GABAergic drug zopiclone.

Sedative-hypnotic drugs commonly used in the elderly may affect functional recovery following cerebrovascular events. Previous research has shown that prolonged exposure to diazepam can interfere with recovery of function and exaggerate tissue loss after brain injury. The present study evaluated the effect of zopiclone, a widely used hypnotic drug, on functional and histological outcome after cortical photothrombosis in aged rats, which might be particularly vulnerable to brain insults and inhibitory sedative-hypnotic drugs. Aged Wistar rats were treated with zopiclone at a dose of 3 mg/kg (i.p., once a day) beginning 4 days before ischemia induction and continuing for 23 days. Sensorimotor recovery was assessed by a new ledged beam-walking test and spatial learning by the Morris water-maze. After a 7-day washout period all rats were administered a single dose of zopiclone (3 mg/kg, i.p.) and retested. Infarct volumes were measured from nitroblue tetrazolium-stained sections at the end of the experiment. Beam-walking data showed that ischemic rats treated with zopiclone were not more impaired than untreated rats. Indeed, they showed fewer faults with the impaired hindlimb than ischemic controls on post-operative day 16. Water-maze performance was not affected by zopiclone. After the washout period a single dose of zopiclone did not worsen forelimb or hindlimb function, but seemed to improve performance in the water-maze test. Cortical infarct volumes were similar in ischemic controls and ischemic rats treated with zopiclone. In conclusion, zopiclone was not detrimental and even seemed to improve behavioral outcome without affecting ischemic damage in aged rats subjected to cortical photothrombosis.

Aging↗

PubMed2005

Effect of cholinergic medication, before and after focal photothrombotic ischemic cortical injury, on histological and functional outcome in aged and young adult rats.

The present study evaluated the effect of galanthamine, a selective competitive cholinesterase inhibitor, on histological and functional outcome after experimental stroke in rats. Cholinesterase inhibitors are commonly used as cognitive enhancers for dementia in aged people, including those who may sustain ischemic attacks. Young adult (5 months) and aged (24 months) rats were treated with saline or galanthamine at a dose of 2.5 mg/kg (i.p., once a day). Drug treatment started 4 days before focal cortical photothrombosis (Rose Bengal, 20 mg/kg) and continued for 21 days thereafter. Sensorimotor recovery was assessed by a new beam-walking test and spatial learning by the Morris water-maze over a 3-week follow-up period. Infarct volumes were measured from nitroblue tetrazolium-stained sections at the end of follow-up. Infarct volumes in the cortex were similar in ischemic controls and ischemic rats treated with galanthamine. In the beam-walking test, there was a transient impairment forelimb function and a permanent impairment in hindlimb after cortical infarct both in young adult and aged rats. Galanthamine treatment did not affect the sensorimotor recovery rate. Analysis of water-maze data did not reveal significant differences in length of path, escape latency, or swim speed between sham-operated, ischemic controls and ischemic rats treated with galanthamine. In conclusion, present findings suggest that the aging brain has considerable plastic capacity to maintain functioning after focal cerebral insults restricted to the motor cortex. Galanthamine is not beneficial with respect to the histological or functional outcome in rats subjected to cortical photothrombosis.

Age Factors↗

PubMed2005

Testing forelimb placing "across the midline" reveals distinct, lesion-dependent patterns of recovery in rats.

We describe a new test of vibrissae-elicited forelimb placing ability that allows testing of sensorimotor integration across the midline. Rats were given unilateral brain lesions using one of three methods: (1) middle cerebral artery occlusion (MCAo) causing significant damage to the cortex and striatum, (2) aspiration lesions to remove tissue from the sensorimotor cortex, and (3) infusions of the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, producing a parkinsonian syndrome. Application of the new test to these animals revealed that with some lesion types, the ability of vibrissae on the unimpaired side of the body to trigger placing in the functionally impaired forelimb recovers before vibrissae on the impaired side can elicit placing. This occurs despite the lack of any apparent vibrissae sensory deficit, since the contralesional vibrissae maintained the ability to trigger placing in the unimpaired forelimb in all lesions studied. Chronically, MCAo-lesioned rats do not place the impaired forelimb upon stimulation of the impaired-side vibrissae, but do place if the vibrissae on the good side are stimulated (i.e., when the placing is triggered "across the midline"). This is in contrast to 6-OHDA-lesioned rats which, consistent with parkinsonian akinesia, cannot place the impaired limb regardless of sensory trigger. Also, differences in the pattern of recovery between MCAo- and aspiration-lesioned rats suggest a possible anatomical substrate for cross-midline placing ability and its recovery. Unlike other tests, cross-midline placing methods can readily distinguish between severe stroke and severe parkinsonism in rats.

Animals↗

PubMed2005

Erythropoietin enhances neurogenesis and restores spatial memory in rats after traumatic brain injury.

Erythropoietin (EPO) is neuroprotective in models of stroke and traumatic brain injury (TBI) when administered prior to or within the first few hours after injury. We seek to demonstrate that EPO also has neurorestorative effects when administered late (i.e., 1 day) after TBI in the rat. Twelve rats were subjected to TBI. Six rats were treated with EPO daily for 14 days starting 1 day after injury, and an additional six rats were treated with saline. Bromodeoxyuridine (BrdU) was administered daily for 14 days. Memory tests using a Morris Water Maze were performed prior to and after injury and treatment. Animals were sacrificed at 15 days after TBI, and their brains were prepared for histological analysis of damage to the dentate gyrus (DG) and for evaluation of newly formed neurons using double labeling of BrdU and MAP-2. The data revealed a significant improvement in spatial memory and significant increase in the number of newly formed neurons with EPO treatment compared with control animals. These data suggest that EPO treatment initiated 1 day after TBI is neurorestorative by enhancing neurogenesis, as well as neuroprotective.

Animals↗