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PubMed2002

Blockade of nigral and pallidal opioid receptors suppresses vacuous chewing movements in a rodent model of tardive dyskinesia.

Chronic neuroleptic treatment leads to the development of tardive dyskinesia in 20-30% of patients. While the pathogenesis of tardive dyskinesia remains elusive, altered opioid peptide function in striatal projection pathways of the basal ganglia has been implicated. Using a rodent model of vacuous chewing movements induced by chronic neuroleptic administration, we investigated regional involvement of opioid transmission in tardive dyskinesia. We examined the role of dynorphin in the direct striatonigral pathway by infusing nor-binaltorphimine, a selective kappa opioid receptor antagonist, into the substantia nigra pars reticulata. As well, infusions of naloxone (a non-specific opioid receptor antagonist), D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr amide (CTOP; a mu opioid receptor antagonist) or naltrindole (a delta opioid receptor antagonist) into the globus pallidus were used to establish the contribution of the striatopallidal pathway. Chronic fluphenazine treatment (25 mg/kg i.m. every 3 weeks for 18 weeks) resulted in a robust increase in vacuous chewing movements. Infusion of nor-binaltorphimine (5.0 nmol) into the substantia nigra pars reticulata significantly attenuated vacuous chewing movements. Infusion of naloxone (0.5 and 2.0 nmol) into the globus pallidus also significantly attenuated vacuous chewing. Infusion of naltrindole into the globus pallidus blocked vacuous chewing at all doses administered (0.5, 1.0, 2.0 nmol) while CTOP was only effective at the two higher doses. From these results we suggest that increases in dynorphin in the direct striatonigral pathway and enkephalin in the indirect striatopallidal pathway following chronic neuroleptic administration are both likely to contribute to tardive dyskinesia.

Animals↗
PubMed1988

Evaluation of CPP, a selective NMDA antagonist, in various rodent models of epilepsy. Comparison with other NMDA antagonists, and with diazepam and phenobarbital.

3-(2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), a novel antagonist at the N-methyl-D-aspartate (NMDA)-preferring subtype of excitatory amino acid receptor, was evaluated in four rodent models of epilepsy, i.e. maximal electroshock seizures and pentylenetetrazol (PTZ)-induced seizures in mice, epileptic gerbils and amygdala-kindled rats. The effect of CPP after systemic (i.p.) injection was compared with that of the clinical antiepileptics, phenobarbital and diazepam, and in gerbils, in addition, with the effect of the NMDA antagonist 2-amino-5-phosphonopentanoate (AP5) and 2-amino-7-phosphonoheptanoate (AP7). CPP, 5 mg/kg i.p., increased the threshold for tonic electroshock seizures but this effect was associated with motor impairment in the chimney test whereas phenobarbital had comparable anticonvulsant potency without motor impairment. The threshold for clonic PTZ seizures was increased by CPP only at high doses (20 mg/kg) which induced ataxia and marked motor impairment in the chimney test, whereas both diazepam and phenobarbital were active in this test at doses which exerted no side-effects. CPP, 2-20 mg/kg i.p., could not reduce the severity or duration of focal and generalized clonic seizures or the duration of amygdalar afterdischarges in the amygdala-kindling model in rats but instead caused ataxia and reduced muscle tone at the higher doses examined. Diazepam and phenobarbital both had anticonvulsant efficacy in this model. CPP at doses of 5-10 mg/kg did not reduce seizure severity in gerbils in which generalized tonic-clonic seizures were induced by air-blast stimulation, but, as in mice and rats, it caused motor impairment.(ABSTRACT TRUNCATED AT 250 WORDS)

Amygdala↗
PubMed2004

Serotonin 2A receptors modulate tail-skin temperature in two rodent models of estrogen deficiency-related thermoregulatory dysfunction.

Menopause-associated thermoregulatory dysfunction, including hot flushes and night sweats, is effectively treated by hormonal therapies that include estrogens. Evidence suggests that estrogen regulates serotonin 2A (5-HT(2A)) receptor expression and that 5-HT(2A) receptors are involved in thermoregulation. Therefore, the role of 5-HT(2A) receptors in thermoregulation was assessed in two rat models of ovariectomy-induced thermoregulatory dysfunction. The first model is based on measurement of the tail-skin temperature (TST) increase following naloxone-induced withdrawal in morphine-dependent ovariectomized (OVX) rats (MD model), while the second model relies on telemetric assessment of diurnal TST changes in ovariectomized rats (telemetry model). Treatment with a 5-HT(2A/2C) receptor agonist, (-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI), prevented the naloxone-induced TST increase in the MD model and restored normal active-phase TST in the telemetry model. The selective 5-HT(2A) receptor antagonist, MDL-100907, had no effect on the naloxone-induced flush when administered alone in the MD model, but it decreased DOI's ability to abate the flush. In the telemetry model, MDL-100907 attenuated the DOI-induced decrease in active-phase TST. Interestingly, MDL-100907 increased TST in both models when given alone, with the TST increase occurring prior to the naloxone-induced flush in the MD model. To evaluate the role of central nervous system (CNS) 5-HT(2A) receptors in TST regulation, DOI was administered in combination with a known peripheral 5-HT(2A/2C) receptor antagonist, xylamidine, in the MD model. Xylamidine had no effect on DOI's ability to abate the naloxone-induced flush. These results indicate that activation of central 5-HT(2A) receptors restores temperature regulation in two rodent models of ovariectomy-induced thermoregulatory dysfunction.

Amidines↗
PubMed2005

Common genetic mechanisms of blood pressure elevation in two independent rodent models of human essential hypertension.

Genetic studies of essential hypertension, a complex, polygenic, and age-dependent disorder, have not been able to completely elucidate the genes responsible for development of the trait. We used a novel strategy to compare gene expression in the adrenal gland of two independent rodent models of human essential hypertension (the spontaneously hypertensive rat, SHR, and the blood pressure high mouse, BPH), with the goal of uncovering shared, common genetic mechanisms of hypertension across mammalian species that might, therefore, be pertinent to human hypertension. We deliberately studied young, 4- to 5-week-old, "prehypertensive" SHR and BPH that had not yet developed complete elevations in blood pressure (BP), so that we could minimize the impact of chronic, sustained BP elevation, age, and other confounding factors on gene expression, therefore increasing the likelihood that differential expression reflects relatively early pathogenic mechanisms in hypertension, rather than later responses to, or compensations for BP elevation. We compared transcript expression patterns of genes orthologous between the rat and the mouse, and presented candidate genes for hypertension that are differentially expressed in the same direction in SHR and BPH (ie, overexpressed in both SHR and BPH, or underexpressed in both SHR and BPH). Then we used a systems biology approach to analyze expression patterns in biochemical pathways and networks to isolate systems involved in hypertension pathology in both SHR and BPH. We found transcript pattern evidence for involvement of several systems in the pathology of hypertension in SHR and BPH: adrenal catecholamines and sympathetic function; steroid hormone synthesis, catabolism, and its contribution to enhanced glucocorticoid sensitivity in SHR; oxidative stress and its role as a common mechanism of vascular and end-organ injury; and intermediary metabolism with global but mechanistically different perturbations in SHR and BPH. Approximately 10% of the differentially expressed orthologous genes we studied shared a common direction of expression in the two hypertensive rodent strains, suggesting fundamental transcriptional mechanisms in common whereby mammals can elevate BP or respond to such elevation; even these shared orthologs spanned a diverse set of biological processes, reinforcing the multifactorial and complex nature of hypertension.

Adrenal Glands↗
PubMed1993

Rodent model of renal ischemia and reperfusion injury: influence of body temperature, seasonal variation, tumor necrosis factor, endogenous and exogenous antioxidants.

The influences of body temperature (T), seasonal variation, antiserum of tumor necrosis factor (TNF), exogenous and endogenous antioxidants on the extent of renal injury in a rodent model were examined. Renal injury was induced by 15-45 min of renal vascular (arterial and venous) occlusion followed by 1-3 days of reperfusion in right-nephrectomized male rats. Plasma creatinine concentration (PC, a reflection of renal injury) was independent of T when T was within 35-40 degrees C (n = 8), but directly related to T when T was within 31-35 degrees C (n = 10). PCs in rats with renal insults performed during October, November and December were similar (600 mcM, n = 10-24), but were higher than that during April (380 mcM, n = 16). Neither TNF antiserum nor exogenous antioxidants (Trolox, ascorbic acid, phytic acid, U-78517F) reduce PC (n = 5-7). However, PC was lower in normal rats than vitamin E deficient rats when subjected to 45 min (329.1 +/- 93.6 mcM vs. 695.9 +/- 37.7 mcM, n = 5-6), but not to 15-30 min of ischemia. In conclusion, renal injury induced by ischemia/reperfusion was T- and season-dependent. An excess of exogenous antioxidants did not reduce, whereas a reduction in endogenous antioxidant vitamin E level enhanced, renal injury.

Animals↗
PubMed1996

Development and characterization of a rodent model of immune-mediated cholangitis.

The cholangiopathies are a group of hepatobiliary diseases in which intrahepatic bile duct epithelial cells, or cholangiocytes, are the target for a variety of destructive processes, including immune-mediated damage. We tested the hypothesis that cholangitis could be induced in rodents by immunization with highly purified cholangiocytes. Inbred Wistar rats were immunized with purified hyperplastic cholangiocytes isolated after bile duct ligation from either syngeneic Wistar or allogeneic Fischer 344 rats; control rats were immunized with bovine serum albumin (BSA) or hepatocytes. After immunization with cholangiocytes, recipient animals developed histologic evidence of nonsuppurative cholangitis without inflammation in other organs; groups immunized with BSA or hepatocytes showed no cholangitis. Immunohistochemical studies revealed that portal tract infiltrates around bile ducts consisted of CD3-positive lymphocytes, some of which expressed major histocompatibility complex class II antigen; B cells and exogenous monocytes/macrophages were essentially absent. Transfer of unfractionated ConA-stimulated spleen cells from cholangiocyte-immunized (but not BSA-immunized) rats into recipients also caused nonsuppurative cholangitis. Moreover, these splenocytes from cholangiocyte-immunized (but not BSA-immunized) rats were cytotoxic in vitro for cultured rodent cholangiocytes; no cytotoxicity was observed against a rat hepatocyte cell line. Also, a specific antibody response in sera of cholangiocyte-immunized rats was demonstrated by immunoblots against cholangiocyte proteins. Finally, cholangiograms in cholangiocyte-immunized rats showed distortion and tortuosity of the entire intrahepatic biliary ductal system. This unique rodent model of experimental cholangitis demonstrates the importance of immune mechanisms in the pathogenesis of cholangitis and will prove useful in exploring the mechanisms by which the immune system targets and damages cholangiocytes.

Animals↗
PubMed2004

Inhibition of gene expression by nucleic acid enzymes in rodent models of human disease.

Nucleic acid enzymes have emerged as a versatile technique for sequence-specific gene silencing in a wide range of cells. However, the question remains as to whether, for example, DNA enzymes and ribozymes are functional in animals. In this chapter, we describe two different rodent models of human diseases--namely, leukemia and chronic heart failure. We specifically reduced Raf-1 expression in leukemic mice using an anti-Raf-1 DNA enzyme. A continuous supply of this catalytic molecule led to a substantial reduction in leukemic-cell burden and survival. Rats with postinfarction heart failure were treated with a DNA enzyme targeting TNFa, and this led to a substantial improvement of cardiac function concomitant with a restoration of the hemodynamic status of the animals. The described protocols should facilitate the in vivo evaluation of other oligonucleotide-based therapy such as small interfering RNAs (siRNAs).

Animals↗
PubMed1991

Methanol poisoning. A rodent model with structural and functional evidence for retinal involvement.

Methanol ingestion can lead to visual impairment, central nervous system dysfunction, or death. The extent of ocular involvement has been difficult to determine because the toxicity is restricted to humans and nonhuman primates due to species differences in methanol metabolism. A rodent model of methanol toxicity recently developed by us was used to evaluate retinal dysfunction in methanol poisoning. Formic acidemia and visual toxic reactions developed in methanol-intoxicated rats. Electroretinographic analysis indicated a significant early deficit in b-wave amplitude followed by a temporally delayed, lesser reduction in a-wave amplitude. Histologic evaluation of the eyes 60 hours after methanol administration revealed generalized retinal edema and vacuolation in the photoreceptors and retinal pigment epithelium. Ultrastructural examination showed swelling and disruption of the mitochondria in photoreceptor inner segments, optic nerve, and the retinal pigment epithelium. These studies document direct retinal involvement in this nonprimate model of methanol toxicity.

Animals↗
PubMed1996

Time-course and treatment response with SNX-111, an N-type calcium channel blocker, in a rodent model of focal cerebral ischemia using diffusion-weighted MRI.

Diffusion-weighted magnetic resonance imaging (DWI) is capable of noninvasively imaging acute cerebral ischemia. We demonstrate the utility of this technique by evaluating SNX-111, a novel N-type calcium channel blocker with potential neuroprotective properties, in a rodent model of transient focal ischemia. Twenty-four Sprague-Dawley rats weighing between 310-350 g underwent occlusion of the middle cerebral artery (MCAO) for 105 min followed by 22.5 h of reperfusion. Thirty minutes following MCAO, animals were randomized to receive SNX-111 5 mg/kg intravenously over 1 h vs. placebo. DWI and T2-weighted MRIs (T2W) were performed at 0.5, 1.5 and 24 h after the onset of ischemia. Area fractions of increased signal intensity on the DWI and T2W images were measured. DWI area fractions at 1.5 and 24 h were also normalized to the initial, pre-treatment scans. Apparent diffusion coefficients (ADC) were calculated from fitted maps. Tri-phenyl tetrazolium chloride (TTC) staining was performed on brains at 24 h and infarct area fractions were measured. SNX-111 treated animals showed significantly improved 1.5-h DWI scan ratios compared to controls (ratios of 1.06 +/- 0.25 vs. 2.98 +/- 0.78 SNX vs. controls respectively, P < 0.05). A trend toward improved DWI ratios was seen by 24 h in the SNX-111 group (2.5 +/- 0.75 vs. 4.12 +/- 1.6, N.S.) DWI, T2W and TTC area fractions at 24 h also showed trends favoring a neuroprotective effect of SNX-111. Bright areas on DWI corresponded to ADC decreases of about 30% compared to the non-ischemic hemisphere. These decreases were the same in both treatment groups and at each time point. DWI, T2W and TTC area fractions at 24 h were strongly correlated (r = 0.98, DWI and TTC; r = 0.99, T2W and TTC; r = 0.97, T2W and DWI, P < 0.0001). We conclude that in this ischemic model, SNX-111 provides early neuroprotection and that serial DWI is a useful way of demonstrating this.

Animals↗
PubMed2002

Evaluation of the mGluR2/3 agonist LY379268 in rodent models of Parkinson's disease.

The aim of the present studies was to examine the ability of a potent, systemically active, selective Group II mGlu receptor (mGluR2/3) agonist, 1R,4R,5S,6R-2-oxa-4-minobicyclo[3.1.0.]hexane-4,6-dicarboxylate (LY379268) to provide both functional relief and neuroprotection in rodent models of Parkinson's disease (PD). In functional studies, intracerebroventricular administration of LY379268 (1, 5, 10, 20 nmol/2 microl) produced a dose-dependent increase in locomotor activity in the reserpine (5 mg/kg ip)-treated rat. In contrast, systemic administration of LY379268 (0.1, 1, 10 mg/kg ip) did not reverse reserpine-induced akinesia and failed to effect rotational behaviour 1 month after unilateral lesioning of the nigrostriatal tract by 6-hydroxydopamine (6-OHDA; 4 microg infused into the substantia nigra (SN)). In neuroprotective studies, animals were treated with LY379268 (10 mg/kg/day ip) either for 7 days following 6-OHDA injection into the SN (4 microg) or for 21 days following 6-OHDA injection into the striatum (10 microg) before measurement of tyrosine hydroxylase immunoreactivity in the striatum and/or SN as an index of neuroprotection. LY379268 provided some protection against nigral infusion of 6-OHDA and also some functional improvement and correction of dopamine turnover was observed. The compound also provided significant protection in the striatum and some protection in the SN against striatal infusion of 6-OHDA. These data suggest that activation of Group II mGlu receptors can provide some protection in models of PD, while their role in providing functional improvement is less clear.

Amino Acids↗
PubMed2005

Activity profile of pregabalin in rodent models of epilepsy and ataxia.

Pregabalin (Lyrica) is a novel amino acid compound that binds with high affinity to the alpha2-delta (alpha2-delta) auxiliary protein of voltage-gated calcium channels. In vivo, it potently prevents seizures, pain-related behaviors and has anxiolytic-like activity in rodent models. The present studies were performed to determine the profile of pregabalin anticonvulsant activity in a variety of mouse and rat models. In the high-intensity electroshock test, pregabalin potently inhibited tonic extensor seizures in rats (ED50 = 1.8 mg/kg, PO), and low-intensity electroshock seizures in mice. It prevented tonic extensor seizures in the DBA/2 audiogenic mouse model (ED50 = 2.7 mg/kg, PO). Its time course of action against electroshock induced seizures in rats roughly followed the pharmacokinetics of radiolabeled drug in the brain compartment. At higher dosages (ED50 1= 31 mg/kg, PO), pregabalin prevented clonic seizures from pentylenetetrazole in mice. In a kindled rat model of partial seizures, pregabalin prevented stages 4-5 behavioral seizures (lowest effective dose = 10 mg/kg, IP), and also reduced the duration of electrographic seizures. Pregabalin was not active to prevent spontaneous absence-like seizures in the Genetic Absence Epilepsy in Rats from Strasbourg (GAERS) inbred Wistar rat strain. Pregabalin caused ataxia and decreased spontaneous locomotor activity at dosages 10-30-fold higher than those active to prevent seizures. These findings suggest that pregabalin has an anticonvulsant mechanism different from the prototype antiepileptic drugs and similar to that of gabapentin except with increased potency and bioavailability. In summary, our results show that pregabalin has several properties that favor treatment of partial seizures in humans.

Animals↗
PubMed2003

Rodent models for HIV-1 infection and disease.

The development of a predictive, small animal model for human immunodeficiency virus type 1 (HIV-1) disease would greatly facilitate the analysis of many aspects of viral infection, pathogenesis and treatment. While numerous small animal models exist which emulate various aspects of HIV-1 infection and/or disease in humans, none of these models support robust HIV-1 replication within the context of an intact immune system. Despite this major limitation, these models have helped to elucidate different aspects of HIV-1 pathogenesis in humans. Moreover, recent advances regarding the underlying nature of the blocks to viral replication in non-human cells have raised the possibility that rodents may be engineered to support HIV-1 infection. This review will focus on recent attempts to develop a rodent model for HIV-1 disease, and will also describe currently available systems for studying HIV-1.

Animals↗
PubMed2004

Bromocriptine reduces lipid peroxidation and enhances spatial learning and hippocampal neuron survival in a rodent model of focal brain trauma.

Oxidative stress is a significant contributor to the secondary sequelae of traumatic brain injury (TBI), and may mediate subsequent neurobehavioral deficits and histopathology. The present study examined the neuroprotective effects of bromocriptine (BRO), a dopamine D2 receptor agonist with significant antioxidant properties, on cognition, histopathology, and lipid peroxidation in a rodent model of focal brain trauma. BRO (5 mg/kg) or a comparable volume of vehicle (VEH) was administered intraperitoneally 15 min prior to cortical impact or sham injury. In experiment 1, spatial learning was assessed in an established water maze task on post-surgery days 14-18, followed by quantification of hippocampal cell survival and cortical lesion volume at 4 weeks. In experiment 2, rats were sacrificed 1 hr post-surgery, and malondialdehyde (MDA), the end product of lipid peroxidation, was measured in the frontal cortex, striatum, and substantia nigra using a thiobarbituric acid reactive substances assay. The TBI+BRO group was significantly more adept at locating a hidden platform in the water maze compared to the TBI+VEH group and also exhibited a greater percentage of surviving CA3 hippocampal neurons. TBI increased MDA in all examined regions of the VEH-treated, but not BRO-treated group versus SHAMs. MDA was significantly decreased in both the striatum (4.22 +/- 0.52 versus 5.60 +/- 0.44 nmol per mg/tissue +/- SEM) and substantia nigra (4.18 +/- 0.35 versus 7.76 +/- 2.05) of the TBI+BRO versus TBI+VEH groups, respectively, while only a trend toward decreased MDA was observed in the frontal cortex (5.44 +/- 0.44 versus 6.96 +/- 0.77). These findings suggest that TBI-induced oxidative stress is attenuated by acute BRO treatment, which may, in part, explain the benefit in cognitive and histological outcome.

Animals↗
PubMed2002

4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1, 3-thiazol-2-amine hydrochloride (SSR125543A), a potent and selective corticotrophin-releasing factor(1) receptor antagonist. II. Characterization in rodent models of stress-related disorders.

The present study investigated the effects of the novel corticotrophin-releasing factor (CRF)(1) receptor antagonist 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A) in a variety of rodent models of anxiety, including conflict procedures (punished drinking and four-plate), exploration models (elevated plus-maze and light/dark), a fear/anxiety defense test battery, and several procedures based on stress-induced changes in physiological (isolation-induced hyperthermia and tail pinch-induced cortical norepinephrine release) or behavioral (social defeat-induced anxiety, maternal separation-induced vocalization) parameters. Moreover, the effects of SSR125543A were investigated in acute (forced swimming) and chronic (chronic mild stress; CMS) models of depression. SSR125543A and the CRF(1) receptor antagonist antalarmin displayed limited efficacy in exploration-based anxiety models. In contrast, both compounds produced clear-cut anxiolytic-like activity in models involving inescapable stress, including the conflict procedures, the social defeat-induced anxiety paradigm and the defense test battery (3-30 mg/kg i.p. or p.o.). These effects paralleled those of the anxiolytic diazepam. In addition, SSR125543A and antalarmin antagonized stress-induced hyperthermia, distress vocalization, and cortical norepinephrine release. In the forced swimming test, 30 mg/kg p.o. SSR125543A and 3 to 30 mg/kg p.o. antalarmin produced clear antidepressant-like effects. These latter results were strengthened by the findings from the CMS, which showed that repeated administration of 10 mg/kg i.p. SSR125543A for 30 days improved the degradation of the physical state, the reduction of body weight gain, and anxiety produced by stress. Together, these data indicate that SSR125543A shows good activity in acute and chronic tests of unavoidable stress exposure, suggesting that it may have a potential in the treatment of depression and some forms of anxiety disorders.

Animals↗
PubMed2005

Meta-analysis of sex differences in rodent models of learning and memory: a review of behavioral and biological data.

The existence of sex differences in the standard rat and mouse models of learning and memory is a controversial and contested topic in the literature. The present meta-analysis of radial maze and water maze experiments was conducted to assess the reliablility and magnitude of sex effects in the standard rodent models of learning and memory. Data were culled from published and unpublished sources. Findings indicate large reliable male advantages for rats in radial maze and water maze protocols. Significant strain differences were also identified. In each paradigm, protocol variations were associated with differential sex effects. For the water maze, smaller male advantages were associated with pretraining regimens and for the radial maze, larger significant male advantages were observed in protocols that included unbaited arms (combined reference and working memory protocols). Mouse studies exhibited a different pattern of sex effects; small female advantages were evident in the water maze, but small male advantages were evident in the radial maze. Together these findings establish the reliability of male advantages in spatial working and reference memory for rats across strains, protocols, ages and rearing environments. The findings also support an important species dichotomy between rats and mice that should be considered when transitioning from rat to mouse models. In light of these results, the biological evidence supporting theoretical explanations of sex differences is reviewed and evaluated.

Animals↗
PubMed2000

Comparison between hypertonic saline and mannitol in the reduction of elevated intracranial pressure in a rodent model of acute cerebral injury.

Clinically both mannitol and hypertonic saline (HTS) have been used successfully to treat elevated intracranial pressure (ICP), although which therapy is superior is yet unclear. Most experimental data have been derived from animal models of brain injury using general anesthesia, which may not be applicable under other conditions. Our laboratory compared the efficacy of single, equi-osmolar bolus doses of HTS and mannitol in reducing elevated ICP in a lightly sedated, unrestrained rodent model of acute brain injury. Sprague-Dawley rats were mask anesthetized for craniectomy and placement of invasive monitors. Following emergence from anesthesia, continuous sedation was provided (0.25% halothane in oxygen). A focal, liquid nitrogen cold lesion was introduced to the right parietal cortex. Animals were continuously monitored and then treated with a single bolus of 0.9% saline (control group) or 11.0 mOsm/kg equivalents of either mannitol or HTS (experimental groups) at time of maximal ICP increase (60 minutes). Both mannitol and HTS reduced ICP, but HTS was more effective-53.9% reduction versus 35.0% (P < .01). The therapeutic action of HTS was also more durable, lasting up to 500 minutes whereas the mannitol treated animals were observed to return to, and overshoot the baseline elevated ICP by 10% to 25% by 120 minutes following dosing (P < .01). Despite these differences, brain water content was similar between groups. We conclude that HTS was more effective in reducing elevated ICP in this awake model of traumatic brain injury.

Analysis of Variance↗
PubMed2002

Protection of dopaminergic nigrostriatal afferents by GDNF delivered by microspheres in a rodent model of Parkinson's disease.

The use of glial cell line-derived neurotrophic factor (GDNF) appears to be a promising strategy to promote survival and function of the nigrostriatal dopaminergic pathway damaged in Parkinson's disease (PD). However, effective intracerebral administration is required for optimal therapeutic benefit and tools to evaluate such therapies must be developed. A rodent model of PD was therefore developed using striatal injection of 6-hydroxydopamine (6-OHDA) with simultaneous implantation of GDNF-delivering microspheres. The effects of GDNF released from microspheres were assessed by classical methods such as amphetamine-induced rotating behavior and tyrosine hydroxylase (TH) immunoreactivity, as well as by quantitative autoradiography using PE2I, a dopamine transporter (DAT) radiotracer, which is also suitable for SPET imaging in humans. 6-OHDA-lesioned animals that received microspheres without GDNF were used as controls. During the first 3 weeks after simultaneous lesion and implantation, the amphetamine-induced rotating behavior of GDNF-treated rats was improved compared to controls and an increase in TH expression (+26%) was measured in the striatum 6 weeks after lesion. In accordance with these results, an increase in striatal PE2I-labeled DAT density was obtained (+17%) after 3 and 6 weeks of treatment. In conclusion, this study demonstrates the neuroprotective action of GDNF delivered by microspheres and suggests that PE2I may be an appropriate radiotracer for use in SPET scintigraphy to follow up treatment of PD in humans.

Animals↗
PubMed1994

Focal brain injury: histological evidence of delayed inflammatory response in a new rodent model of focal cortical injury.

Cortical contusions are one of the most common characteristics in head injury and are regarded by many as the hallmark of significant injury. No experimental study has clarified the roles of mechanical forces, haemorrhage and ischaemia in the process of progressive acute brain damage and later neurobehavioural dysfunction. We have devised a new, simple reproducible rodent model of focal cortical injury which employs a 'pure' mechanical/physical force applied through the intact dura. Using this model we have investigated the time course and pattern of changes in neurons, glia and microvasculature. With the exception of haemorrhage, this model closely reproduces the light- and electron microscopy features of human contusion. In the absence of perivascular haemorrhage we have demonstrated delayed perivascular protein leakage and polymorphonuclear-leukocyte infiltration of the damaged cortex. We postulate that a component of the delayed blood brain barrier breakdown demonstrated in human focal head injury (which may contribute to swelling and brain damage) is due to an acute inflammatory response, the magnitude of which is dependent on the amount of tissue injury.

Acute-Phase Reaction↗