Disruption In Rats Research Articles

Neuromuscular recovery pattern after medial collateral ligament disruption in rats

The medial collateral ligament (MCL) is one of the most injured ligaments during sport activities. The resulting joint damage effects on neuromuscular system remain unclear. Thus this study was designed to assess the changes in neuromuscular properties of vastus medialis muscle after MCL transection. Complete rupture of MCL was performed on rats, and dynamic functional assessment during locomotion was achieved before and once a week from 1-5 wk postlesion. Twitch properties and metabo- and mechanosensitive afferent fiber responses to specific stimuli were measured 1, 3, and 5 wk after MCL transection. Results indicated that maximum knee angle measured during the stance phase of the gait cycle was decreased during 3 wk after MCL injury and then recovered. Minimum knee angle measured during the stance phase was decreased during 2 wk and showed compensatory effects at week 5. A stepwise decrease in maximum relaxation rate-to-amplitude ratio concomitant with a stepwise increase in half-relaxation time were observed following MCL injury. Variations in metabosensitive afferent response to chemical (KCl and lactic acid) injections were decreased at week 1 and recovered progressively from week 3 to week 5 postlesion. Recovery of the mechanosensitive afferent response to vibrations was not totally complete after 5 wk. Our data indicate that alteration of the sensory pathways from the vastus medialis muscle could be considered as a source of neuromuscular deficits following MCL transection. Our results should be helpful in clinical purpose to improve the knowledge of the influence exerted by ligament rupture on the motor system and permit development of rehabilitation protocols and exercises more appropriate for recovery of functional stability.

Thalidomide decreases intrahepatic resistance in cirrhotic rats

Increased intrahepatic resistance (IHR) within cirrhotic liver is caused by increased endotoxemia, cytokines tumor necrosis factor-α (TNF-α), vasoconstrictor thromboxane A 2 (TXA 2), and disrupted microvasculatures. We evaluated the effects of thalidomide-related inhibition of TNF-α upon the hepatic microcirculation of cirrhosis in rats. Portal venous pressure (PVP), hepatic TNF-α, expression of thromboxane synthase (TXS), and leukocyte common antigen (LCA) were measured in bile-duct-ligated (BDL) rats receiving 1 month of thalidomide (BDL-thalido rats). Portal perfusion pressure (PPP), IHR, and hepatic TXA 2 production were measured in the isolated liver perfusion system. Intravital microscopy was used to examine hepatic microvascular disruptions. In BDL-thalido rats, PVP, PPP, IHR, hepatic TXA 2 and TNF-α, hydroxyproline content, expression of TXS and LCA, and LPS-induced leukocyte recruitment were significantly decreased. Conversely, hepatic microvascular density and perfused sinusoids were significantly increased. Thalidomide decreased PVP and IHR by reducing hepatic TXA 2 and improving hepatic microvascular disruptions in rats with biliary cirrhosis.

Proapoptotic and prepulse inhibition (PPI) disrupting effects of Hypericum perforatum in rats

Ethnopharmacological relevance St. John's wort extract is commonly used as a wound healing, anti-inflammatory, anxiolytic, diuretic, antibiotic, antiviral and cancer chemoprotective agent. It also has nootropic and/or antiamnestic effects. Aim of the study Prepulse inhibition (PPI) of startle response is a valuable paradigm for sensorimotor gating processes. A previous study indicated that single administration of St. John's wort extract (500 mg/kg) caused PPI disruption in rats. The effect of antiamnestic doses of the extract on PPI has not been investigated despite the coexistence of impaired memory and PPI deficit in some neurological disorders. Materials and methods The effects of acute (500 mg/kg) and chronic (200 mg/kg for 3 days) administration of St. John's wort extract were investigated for its antiamnestic activity. The effects of administration of the antiamnestic dose of the extract and hyperforin, its main active component, were tested on PPI of an acoustic startle response in rats. This study also investigated the proapoptotic effect of hyperforin in animals, demonstrating PPI deficit, by electrophoresis of DNA isolated from selected brain areas. Results Disruption of PPI resulted after treatment of rats with an antiamnestic dose of the extract (200 mg/kg for 3 days) and with hyperforin. Gel electrophoresis showed DNA fragmentation of the cortices of hyperforin-treated animals exhibiting PPI deficit. Conclusions The exacerbating effect of St. John's wort extract on PPI deficit may provide a limitation for using the extract to manage cognitive disturbance in psychotic and Huntington's disease patients manifesting PPI deficit.

Evidence for a critical role of entorhinal cortex at pre‐exposure for latent inhibition disruption in rats

Latent inhibition (LI), that is the decrease in conditioned response induced by the repeated nonreinforced pre-exposures to the to-be-conditioned stimulus, is disrupted by entorhinal cortex (EC) lesions. The mechanism involved in this disruption is unknown, and in particular the experimental stage (pre-exposure or conditioning) at which the integrity of EC is necessary has to be determined. The purpose of this study was to address this issue by using reversible inactivation of the EC by local micro-infusion of tetrodotoxin (TTX). TTX was infused either before the pre-exposure phase, before the conditioning phase, or before both phases. LI was unaffected in rats that received TTX before conditioning or before both pre-exposure and conditioning. In contrast, LI was disrupted in rats that received TTX before pre-exposure only. These results are discussed in the framework of LI models.

Lepidium meyenii (Maca) reversed the lead acetate induced—Damage on reproductive function in male rats

Rats were treated with 0, 8, 16 and 24 mg/kg of lead acetate (LA) (i.p.) for 35 days with or without Maca. Maca was co-administrated orally from day 18 to day 35. The lengths of stages of the seminiferous epithelium were assessed by transillumination. Also, sex organ weights, testicular and epididymal sperm count, sperm motility, daily sperm production, sperm transit rate and serum testosterone levels were measured. Lead acetate treatment resulted in a dose–response reduction of lengths of stages VIII and IX–XI, and serum testosterone levels. However, rats treated with 8 and 16 mg/kg but not 24 mg/kg of lead acetate showed a low number of testicular spermatids, low daily sperm production (DSP) and low epididymal sperm count. Administration of Maca to rats treated with lead acetate resulted in higher lengths of stages VIII and IX–XI with respect to lead acetate-treated rats. Moreover, treatment with Maca to lead acetate-treated rats resulted in lengths of stages VIII and IX–XI similar to the control group. Maca administration also reduced the deleterious effect on DSP caused by lead acetate treatment. Maca prevented LA-induced spermatogenic disruption in rats and it may become in a potential treatment of male infertility associated with lead exposure.

Toxicokinetic parameters of toluene in the rat and guinea pig: a comparative study

Toluene is the most widely used industrial solvent. It has been shown to cause cochlear disruptions in rats but markedly less ototoxic effects in guinea pigs. Susceptibility to the ototoxic properties of toluene is, therefore, species specific. In recent publications, an important difference in the solvent concentration in blood has been identified when rats and guinea pigs were exposed in strictly identical experimental conditions. Solvent concentrations in blood were greater in rats than in guinea pigs. The present studies were designed to compare blood affinity and toxicokinetic parameters of toluene in an attempt to understand the susceptibility differences in both species. The in vitro experiment, in which the headspace concentration of toluene was measured within a sealed vial containing blood, highlighted the greater toluene partition coefficient in rat than in guinea pig blood. The in vivo experiment showed that 10 min after a single intravenous administration of 28 μL of toluene, the solvent concentration is approximately two-fold lower in guinea pig than in rat blood. Based on the toxicokinetic parameters of toluene and on the relative partition coefficient of toluene in blood, it seems plausible that guinea pigs are not susceptible to organic solvents because the solvent concentration in blood does not reach the concentration required to induce permanent damage. Attempts to explain differences of vulnerability between the rat and guinea pig are addressed in the present paper.

P.3.073 Bifeprunox: providing a new option for treating psychosis

Background: The disruption of prepulse inhibition of acoustic startle (PPI) is an animal model for some aspects of schizophrenia. Phencyclidine causes psychotomimetic symptoms in human and disrupts PPI in animals, however, the mechanism underlying this disruption remains unclear. The present experiment tested the hypothesis that serotonin 2A receptor blocking property of drugs reverses the phencyclidine-induced PPI disruption.Methods: The ED50 value of spiperone, haloperidol, chlorpromazine, clozapine, risperidone, olanzapine, seroquel, pipamperone, mianserin, or desipramine to reverse the phencyclidine- or apomorphine-induced PPI disruption in rats was determined. Then the correlation between the ED50 value and the affinity for the serotonin 2A, 2C, dopamine D2, or α-1 receptor of each drug was examined.Results: The ED50 value of the drugs to reverse the phencyclidine-induced PPI disruption was significantly correlated with the affinity for the serotonin 2A receptor, but not for the dopamine D2, serotonin 2C, or α-1 receptor of each drug. In contrast, the ED50 value of the drugs to reverse the apomorphine-induced PPI disruption was significantly correlated with the affinity for the dopamine D2 receptor, but not for the serotonin 2A receptor.Conclusions: An activation of serotonin 2A receptors would mediate the phencyclidine-induced PPI disruption.

Effects of acute treatment with antidepressant drugs on sensorimotor gating deficits in rats.

Schizophrenic patients have a deficit in prepulse inhibition (PPI) which can be modelled in rats by administration of direct or indirect dopamine (DA) receptor agonists and N-methyl-D-aspartate (NMDA) receptor antagonists. Moreover, antipsychotics reverse the disruptive effect of DA agonists and NMDA receptor antagonists in this rat model. Consequently, this model is considered as predictive of antipsychotic action in the clinic. However, the effect of compounds, such as antidepressants, used for other psychiatric disorders but also administered to patients with schizophrenia has not been well investigated in this model. Antidepressants have been suggested not to affect PPI in humans. Thus, antidepressants are not expected to antagonise PPI disruption in rats, and should normally be used as negative controls in this model. To investigate the effects of three antidepressant compounds, a serotonin reuptake inhibitor, a dopamine reuptake inhibitor, and a noradrenaline reuptake inhibitor in the rat PPI model. The effect of acute treatment with citalopram, bupropion and desipramine on d-amphetamine-disrupted and phencyclidine (PCP)-disrupted PPI in rats was investigated. Ziprasidone was tested as a positive control. None of the antidepressants, in contrast to ziprasidone, reversed PCP-disrupted PPI in rats. Both desipramine and ziprasidone normalised d-amphetamine-disrupted PPI, while citalopram and bupropion were inactive. PCP-disrupted PPI in rats was less sensitive to false positives than the d-amphetamine-disrupted PPI model, based on the antidepressants tested in this study.

Hypoxia-induced apoptosis of dorsal root ganglion neurons is associated with DNA damage recognition and cell cycle disruption in rats

The metabolic effects of hyperglycemia and hypoxia are important in the pathogenesis of diabetic neuropathy. We demonstrated apoptosis in dorsal root ganglion neurons in vitro by employing an oxygen-glucose deprivation model that uses dorsal root ganglia incubated in room air (pO 2=150 torr) followed by hypoxic conditions (pO 2=7.6 torr). Apoptosis was confirmed by demonstrating caspase-3 activation by immunocytochemistry. Immunocytochemistry and western blot analysis demonstrated an increase in activated p53, suggesting that DNA damage was occurring. Cell cycle disruption was examined by cyclin D1 expression. Neuronal death was associated with up-regulation of markers associated with DNA damage and aberrant entry into G 1 of the cell cycle.

Effect of maternal NG‐nitro‐l‐arginine administration on fetal growth and hypoxia‐induced changes in newborn rats

Nitric oxide (NO) inhibition with NG-nitro-l-arginine methyl ester (l-NAME) in the last trimester of pregnancy caused intrauterine growth retardation and hind-limb disruptions in rats. In the present study, the effect of maternal NO inhibition with NG-nitro-l-arginine (l-NNA) on hypoxic newborn rats was investigated. Timed-pregnant rats were obtained on gestational day 17. Four groups of rats were used: control, hypoxic, l-NNA and l-NNA + hypoxic groups. In the last two groups, l-NNA (2 mg/kg bolus, i.p.) was administered to the mothers of pups antenatally on 3 consecutive days. Hypoxia was induced in newborn rats by breathing of a mixture of 8% oxygen and 92% nitrogen for 3 h. Pups were then allowed to inhale normal atmospheric air for 30 min. All newborn rats were decapitated on the first day of life after hypoxia and reoxygenation. Brain, heart, lung, liver, kidney and intestinal tissues were studied biochemically. Hypoxia-induced biochemical changes were determined by measuring lipid peroxidation. Histopathologic examination of lung tissue was performed. Nitric oxide synthase inhibition in pregnancy did not cause fetal growth retardation. Hypoxia increased lipid peroxidation in all tissues except the heart; this increase was decreased by maternal l-NNA administration in brain, lung, liver and kidney tissues. However, lipid peroxidation was increased by NO synthase inhibition in the intestines. In the lungs, pulmonary hemorrhage was observed in the hypoxic group. Minimal pulmonary hemorrhage was detected in the l-NNA and l-NNA + hypoxic groups. These data suggest that antenatal administration of an NO synthase inhibitor acts as both a destructive and protective agent in hypoxic newborn rats.

D1-receptor drugs and cocaine-seeking behavior: investigation of receptor mediation and behavioral disruption in rats.

Dopamine D1-receptor antagonists and agonists both attenuate cocaine-seeking behavior (i.e., operant responding in the absence of cocaine reinforcement) elicited by a cocaine prime or cocaine-paired stimuli. It remains unclear whether these effects are D1-receptor mediated. The present study tested whether a D1 antagonist (SCH-23390) would reverse the attenuating effects of a D1 agonist (SKF-81297) on cocaine-seeking behavior and whether behavioral disruption is involved in these effects. Rats trained to press a lever for cocaine reinforcement with light and tone cues paired with each infusion underwent daily extinction sessions during which responding had no scheduled consequences (i.e., neither cocaine nor the cocaine-paired stimulus complex was available). After responding diminished, the effects of the D1 antagonist on the dose-response functions of the D1 agonist for reinstatement of cocaine-seeking behavior by response-contingent cue presentations or cocaine priming were examined. A separate experiment assessed the effects of the agonist on the dose-response function of the antagonist for cue reinstatement. Stereotyped behavior and activity were also measured during each test session. The attenuating effects of SKF-81297 on cocaine-seeking behavior during cocaine-primed reinstatement were reversed by co-administration of SCH-23390. However, no evidence for reversal of the attenuation during cue reinstatement was found even though agonist-induced stereotypy and antagonist-induced hypoactivity were reversed by co-administration of the two drugs during the same test session. The findings suggest that the attenuating effects of D1-receptor drugs on cocaine-seeking behavior during cocaine reinstatement are mediated by dopamine D1 receptors; however, it remains unclear whether the effects of these drugs on cocaine-seeking behavior during cue reinstatement are D1-receptor mediated. Nevertheless, it is evident that the attenuation of cocaine-seeking behavior by these drugs is not simply due to behavioral disruption.

Quantitative Analysis of Papaverine-Mediated Blood–Brain Barrier Disruption in Rats

The blood–brain barrier (BBB) is a permeability barrier of interconnected brain capillary endothelial cells. Intraarterial infusion of papaverine relieves cerebral vasospasms by inhibiting smooth muscle contractions and it may simultaneously lead to a disruption of BBB permeability. To date, the mechanism underlying this phenomenon and the quantification of BBB disruption remains elusive. We first examined the changes in cerebrovascular permeability after an intracarotid infusion of papaverine (0.20%) in rats by an in situ brain perfusion technique. We then demonstrated that changes in cerebrovascular permeability depend on the concentration of papaverine. This is the first study in which the degree of BBB disruption was accurately quantified in terms of [14C]sucrose and it was demonstrated that papaverine has a prolonged effect on cerebrovascular permeability. This result suggests the importance of in vivo experiments for a precise evaluation of permeability for many other agents, particularly for the central nervous system.

Quantification of early blood–brain barrier disruption by in situ brain perfusion technique

Osmotic disruption is currently being used to circumvent the blood–brain barrier (BBB) and enhance the delivery of therapeutic molecules in human brains. To date, however, the time course during the early phase of disruption has not been clarified. In order to demonstrate the rapid change in cerebrovascular permeability after BBB disruption in rats, we developed a method of in situ brain perfusion to demonstrate the earliest reversibility in cerebrovascular permeability. Osmotic BBB disruption was attained by intracarotid infusion of hypertonic mannitol. Perfusate containing [ 14C]-sucrose was infused at different time points following osmotic stress followed by measuring cerebrovascular permeability. The earliest BBB disruption was seen to occur 5 min after osmotic stress, after which the exact time course of cerebrovascular reversibility was studied. The protocol reported here, in contrast with those reported in previous studies, was shown to be qualitative, simple, and fast. In addition, the method can be applied to measure any low BBB permeability molecules. This protocol should be helpful for any research focused on enhancing drug delivery into the brain following osmotic BBB disruption.

Memory disruption in rats with nigral lesions induced by MPTP: a model for early Parkinson's disease amnesia

Intra-nigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) caused a lesion in the substantia nigra, compact part (SNc) and a specific loss of dopamine and its metabolites in the striatum of rats. The animals were then tested in the two-way active avoidance task. MPTP-treated animals presented lower learning scores in the training and test sessions, an effect that was not caused by motor impairment or by a decreased sensitivity to footshock since their reaction time to the footshock (unconditioned stimulus — UCS) was not reduced. These lower scores were also not attributable to lower acoustic sensitivity or to a slowing in the association of the sound cue (conditioned stimulus — CS) with the UCS since the reaction time to the CS in the active avoidance response did not differ between MPTP-treated and control groups. Therefore, these results are more properly attributable to an impairment of the memory acquisition and retention processes. In addition, this study is presented as a model of early Parkinson's Disease amnesia and is discussed in terms of the importance of the nigrostriatal pathway to memory acquisition and storage processes.

The effects of the Na +/Ca ++ exchange blocker on osmotic blood–brain barrier disruption

Osmotic disruption of the blood–brain barrier (BBB) by mannitol is currently being used to enhance drug delivery in human brains. Despite clinical and experimental interest, to date the time course in the early phase of disruption has not been accurately identified. The mechanism in barrier closure also remains elusive. We first studied the rapid change in cerebrovascular permeability after BBB disruption in rats, and then demonstrated that the Na +/Ca ++ exchange blocker (KB-R7943) prolongs osmotic disruption. Osmotic BBB disruption was attained by using intra-arterial infusion of hypertonic mannitol in Sprague–Dawley (SD) rats. To measure the changes in cerebrovascular permeability, perfusate containing [ 14C]-sucrose was infused intra-arterially at different time points following osmotic stress. Cerebrovascular permeability was then measured with the in situ brain perfusion technique. This is the first in vivo study demonstrating that osmotic disruption is prolonged by the Na +/Ca ++ exchange blocker, which did not affect the peak level of BBB disruption. The exact time course of cerebrovascular reversibility was studied and the earliest BBB disruption was seen to occur 5 min after osmotic stress. Histopathological examination after osmotic disruption with the Na +/Ca ++ exchange blocker showed no neuronal damage in rat brains. Our findings represent important experimental information regarding pharmacological manipulation of BBB disruption. The possibility of prolonging the transient opening of the BBB has major clinical implications.

Involvement of serotonin 2A receptors in phencyclidine-induced disruption of prepulse inhibition of the acoustic startle in rats

Background: The disruption of prepulse inhibition of acoustic startle (PPI) is an animal model for some aspects of schizophrenia. Phencyclidine causes psychotomimetic symptoms in human and disrupts PPI in animals, however, the mechanism underlying this disruption remains unclear. The present experiment tested the hypothesis that serotonin 2A receptor blocking property of drugs reverses the phencyclidine-induced PPI disruption. Methods: The ED 50 value of spiperone, haloperidol, chlorpromazine, clozapine, risperidone, olanzapine, seroquel, pipamperone, mianserin, or desipramine to reverse the phencyclidine- or apomorphine-induced PPI disruption in rats was determined. Then the correlation between the ED50 value and the affinity for the serotonin 2A, 2C, dopamine D 2, or α-1 receptor of each drug was examined. Results: The ED 50 value of the drugs to reverse the phencyclidine-induced PPI disruption was significantly correlated with the affinity for the serotonin 2A receptor, but not for the dopamine D 2, serotonin 2C, or α-1 receptor of each drug. In contrast, the ED 50 value of the drugs to reverse the apomorphine-induced PPI disruption was significantly correlated with the affinity for the dopamine D 2 receptor, but not for the serotonin 2A receptor. Conclusions: An activation of serotonin 2A receptors would mediate the phencyclidine-induced PPI disruption.

The influence of anesthetic choice, PaCO2, and other factors on osmotic blood-brain barrier disruption in rats with brain tumor xenografts.

Increasing the delivery of therapeutic drugs to the brain improves outcome for patients with brain tumors. Osmotic opening of the blood-brain barrier (BBB) can markedly increase drug delivery, but achieving consistent, good quality BBB disruption (BBBD) is essential. We evaluated four experiments compared with our standard isoflurane/O2 protocol to improve the quality and consistency of BBBD and drug delivery to brain tumor and normal brain in a rat model. Success of BBBD was assessed qualitatively with the large molecular weight marker Evans blue albumin and quantitatively by measuring delivery of the low molecular weight marker [3H]-methotrexate. With isoflurane/O2 anesthesia, the effects of two BBBD drugs of different osmolalities were evaluated at two different infusion rates and infusion durations. Arabinose was superior to saline (P = 0.006) in obtaining consistent Evans blue staining in 16 of 24 animals, and it significantly increased [3H]-methotrexate delivery compared with saline in the tumor (0.388 +/- 0.03 vs 0.135 +/-0.04; P = 0.0001), brain around the tumor (0.269 +/- 0.03 vs 0.035 +/- 0.03; P = 0.0001), brain distant to the tumor (0.445 +/- 0.05 vs 0.034 +/- 0.07; P = 0.001), and opposite hemisphere (0.024 +/- 0.00 vs 0.016 +/- 0.00; P = 0.0452). Forty seconds was better than 30 s (P = 0.0372) for drug delivery to the tumor. Under isoflurane/O2 anesthesia (n = 30), maintaining hypocarbia was better than hypercarbia (P = 0.025) for attaining good BBBD. A propofol/ N2O regimen was compared with the isoflurane/O2 regimen, altering blood pressure, heart rate, and PaCO2 as covariates (n = 48). Propofol/N2O was superior to isoflurane/O2 by both qualitative and quantitative measures (P < 0.0001). Neurotoxicity and neuropathology with the propofol/N2O regimen was evaluated, and none was found. These data support the use of propofol/N2O along with maintaining hypocarbia to optimize BBBD in animals with tumors. Propofol/N2O anesthesia may be better than isoflurane/O2 for optimizing osmotic blood-brain barrier disruption for delivery of chemotherapeutic drugs to brain tumor and normal brain.

Effect of 192IgG-saporin injections into the nucleus basalis magnocellularis on acquisition and performance of a go/no-go procedure in the rat

The effects of injections of low (105 ng) and high (210 ng) doses of the cholinergic-selective neurotoxin 192IgG-saporin (SAP) into the nucleus basalis magnocellularis on both the acquisition and performance of a go/no-go operant task in Long-Evans rats were examined and were correlated with regional changes in choline acetyltransferase (ChAT) activity. The go/no-go procedure rewards a rat for pressing a lever on alternate trials, with intertrial intervals (i.e., delays) of 5, 20, and 40 sec. Over a period of 15 days, normal rats rapidly become proficient in this task, so that the ratio of latency to the first press on the rewarded go trial to latency to press on the nonrewarded no-go trial is significantly less than 1. With injections made prior to acquisition, there was a significant disruptive effect of both doses of SAP that was not delay dependent. In previously trained rats, SAP disrupted performance during a 2-week training period, with the high dose of SAP having a more pronounced effect. A uniform 60% reduction of cortical ChAT activity relative to control was found after either high- or low-SAP injections; however, there was a dose-dependent reduction in hippocampal ChAT activity with SAP treatment (low dose [20%–29%] and high dose [39%–44%]). Thus, the dose-dependent disruption in rats trained prior to injection may be related to combined cortical and hippocampal cholinergic deficits. The presence of an impairment at even the shortest delay suggests that impaired working memory may play only a minor role in the go/no-go deficit produced by disruption of the basal forebrain cholinergic system and that impaired attention may be more important.

The Influence of Anesthetic Choice, PaCO2, and Other Factors on Osmotic Blood-Brain Barrier Disruption in Rats with Brain Tumor Xenografts

Increasing the delivery of therapeutic drugs to the brain improves outcome for patients with brain tumors.Osmotic opening of the blood-brain barrier (BBB) can markedly increase drug delivery, but achieving consistent, good quality BBB disruption (BBBD) is essential. We evaluated four experiments compared with our standard isoflurane/O (2) protocol to improve the quality and consistency of BBBD and drug delivery to brain tumor and normal brain in a rat model. Success of BBBD was assessed qualitatively with the large molecular weight marker Evans blue albumin and quantitatively by measuring delivery of the low molecular weight marker [(3) H]-methotrexate. With isoflurane/O (2) anesthesia, the effects of two BBBD drugs of different osmolalities were evaluated at two different infusion rates and infusion durations. Arabinose was superior to saline (P = 0.006) in obtaining consistent Evans blue staining in 16 of 24 animals, and it significantly increased [(3) H]-methotrexate delivery compared with saline in the tumor (0.388 +/- 0.03 vs 0.135 +/- 0.04; P = 0.0001), brain around the tumor (0.269 +/- 0.03 vs 0.035 +/- 0.03; P = 0.0001), brain distant to the tumor (0.445 +/- 0.05 vs 0.034 +/- 0.07; P = 0.001), and opposite hemisphere (0.024 +/- 0.00 vs 0.016 +/- 0.00; P = 0.0452). Forty seconds was better than 30 s (P = 0.0372) for drug delivery to the tumor. Under isoflurane/O2 anesthesia (n = 30), maintaining hypocarbia was better than hypercarbia (P = 0.025) for attaining good BBBD. A propofol/N (2) O regimen was compared with the isoflurane/O2 regimen, altering blood pressure, heart rate, and PaCO2 as covariates (n = 48). Propofol/N2 O was superior to isoflurane/O2 by both qualitative and quantitative measures (P < 0.0001). Neurotoxicity and neuropathology with the propofol/N2 O regimen was evaluated, and none was found. These data support the use of propofol/N2 O along with maintaining hypocarbia to optimize BBBD in animals with tumors. Implications: Propofol/N2 O anesthesia may be better than isoflurane/O2 for optimizing osmotic blood-brain barrier disruption for delivery of chemotherapeutic drugs to brain tumor and normal brain. (Anesth Analg 1999;88:559-67)

Investigation of blood-brain barrier permeability to magnetite-dextran nanoparticles (MD3) after osmotic disruption in rats.

The permeability of experimentally disrupted blood-brain barrier (BBB) to superparamagnetic nanoparticles (MD3) was studied in rats. BBB opening was induced by intracarotid injection of mannitol. One hundred eighty rats were used for the study. Rats were examined at two time points, 30 minutes and 12 hours after intracarotid mannitol injection. Different preparations intravenously injected 30 minutes before rat sacrifice were used for characterization of BBB disruption. BBB integrity was determined with 99mTc-diethylenetriamine pentaacetic acid (DTPA) and 99mTc-albumin. Iron oxide-glucose particles (12-nm mean diameter), 99mTc-labeled lecithin-cholesterol liposomes of three different sizes (50, 100, and 200 nm), and polyethylene glycol (PEG)-coated 99mTc liposomes (50 nm) were used for investigations of the dependence of BBB permeability on particle system size or surface. Magnetite-dextran nanoparticles (MD3) were evaluated as superparamagnetic contrast agent to monitor with magnetic resonance imaging (MRI) the BBB breakdown. In vitro T1 and T2 relaxation times of the brain tissue were measured at 40 MHz and 37 degrees C, and T2-weighted MR images were acquired at 0.5 T. After intracarotid mannitol infusion, as expected, the BBB breakdown was immediate and temporary as judged by soluble molecule diffusion. MD3 nanoparticles crossed the BBB 12 hours after intravenous mannitol injection, at a time when brain permeability for molecules or small particles returns to normal. Magnetite crystals were found in cytoplasmic vesicles of glial cells. On MRI, signal intensity decreased after injection of MD3, even 12 hours after mannitol injection. This particularity could be useful in the study of focal pathological lesions accompanied by BBB permeability modifications. In such conditions, superparamagnetic particle contrast agents could be caught by the BBB, allowing the observation of impaired BBB areas without detectable cellular lesions.