Effects of prenatal gamma-irradiation on the astrocyte proliferation in response to injury in the brain of 6-day-old rat

Pregnant Wistar rats were exposed to a single 1.0 Gy dose of gamma rays on gestational days 13, 15, 17 or 19 (E13, E15, E17 and E19, respectively). A mechanical injury was made in the cerebral hemisphere of their 6 day-old male offsprings. The injured rats were injected with [3H]thymidine on day 1 or 2 after injury and killed 4 h after the injection. Brain sections were immunostained for glial fibrillary acidic protein (GFAP) or S-100beta protein, subjected to autoradiography and examined microscopically to record proliferating astrocytes. The intensity of astrocyte proliferation in response to injury showed a gradual decrease from the level maximal in brains irradiated on E13 to minimal in those irradiated on E19. The changes were regarded as being related to the stage of prenatal development when irradiation of the brain was performed.     

Muscarinic cholinergic receptor binding in rat brain following traumatic brain injury

Recent evidence suggests that excessive activation of muscarinic cholinergic receptors (mAChRs) contributes significantly to the pathophysiological consequences of traumatic brain injury (TBI). To examine possible alterations in mAChRs after TBI, the affinity (Kd) and maximum number of binding sites (Bmax) of mAChRs in hippocampus, neocortex, brain stem and cerebellum were determined by [3H]QNB binding. Three groups of rats were examined: 1 h post-TBI (n = 21), 24 h post-TBI (n = 21) and sham-injured rats (n = 21). Kd values were significantly higher in hippocampus and brain stem at 1 but not 24 h post-TBI compared with sham-injured controls (P < 0.05). Kd values did not significantly differ in neocortex and cerebellum at 1 or 24 h post-TBI compared with sham-injured controls. Bmax values did not significantly differ in any brain areas at 1 or 24 h post-TBI compared with sham-injured controls. These results show that TBI significantly decreases the affinity of mAChRs in hippocampus and brain stem at an early stage post-TBI, which may contribute to desensitization of mAChRs after TBI. The findings of no change in Bmax values are consistent with a transient elevation in ACh concentrations after TBI.     

Distribution and temporal regulation of the immune response in the rat brain to intracerebroventricular injection of interferon-gamma

The response to intracerebroventricular administration of interferon (IFN)-gamma was examined in the adult Wistar rat brain: major histocompatibility complex (MHC) antigens class I and II, CD8 and CD4 antigens, and the macrophage/microglia antigen OX42 were analyzed in respect to saline-injected cases over 1 week. The glial cell type expressing MHC antigens was characterized with double labeling. IFN-gamma was thus found to induce MHC class I and II expression in microglia, identified by tomato lectin histochemistry, and not in GFAP-immunostained astrocytes. MHC antigen-expressing microglia was detected in the periventricular parenchyma, several fields of the cerebral cortex, cerebellum, major fiber tracts, and brainstem superficial parenchyma. Different gradients of density and staining intensity of the MHC-immunopositive elements were observed in these regions, in which MHC class I antigens persisted up to 1 week, when MHC class II induction had declined. Quantitative analysis pointed out the proliferation of OX42-immunoreactive cells in periventricular and basal brain regions. CD8+ T cells were observed in periventricular regions, basal forebrain, and fiber tracts 3 days after IFN-gamma injection and their density markedly increased by 7 days. CD4+ T cells were also seen and they were fewer than CD8+ ones. However, numerous CD4+ microglial cells were observed in periventricular and subpial regions, especially 1 week after IFN-gamma injection. Our data indicate that this proinflammatory cytokine mediates in vivo microglia activation and T cell infiltration in the brain and that the cells involved in this immune response display a regional selectivity and a different temporal regulation of antigen expression.     

Post-traumatic brain hypothermia reduces histopathological damage following concussive brain injury in the rat

The purposes of this study were (1) to document the histopathological consequences of moderate traumatic brain injury (TBI) in anesthetized Sprague-Dawley rats, and (2) to determine whether post-traumatic brain hypothermia (30 degrees C) would protect histopathologically. Twenty-four hours prior to TBI, the fluid percussion interface was positioned over the right cerebral cortex. On the 2nd day, fasted rats were anesthetized with 70% nitrous oxide, 1% halothane, and 30% oxygen. Under controlled physiological conditions and normothermic brain temperature (37.5 degrees C), rats were injured with a fluid percussion pulse ranging from 1.7 to 2.2 atmospheres. In one group, brain temperature was maintained at normothermic levels for 3 h after injury. In a second group, brain temperature was reduced to 30 degrees C at 5 min post-trauma and maintained for 3 h. Three days after TBI, brains were perfusion-fixed for routine histopathological analysis. In the normothermic group, damage at the site of impact was seen in only one of nine rats. In contrast, all normothermic animals displayed necrotic neurons within ipsilateral cortical regions lateral and remote from the impact site. Intracerebral hemorrhagic contusions were present in all rats at the gray-white interface underlying the injured cortical areas. Selective neuronal necrosis was also present within the CA3 and CA4 hippocampal subsectors and thalamus. Post-traumatic brain hypothermia significantly reduced the overall sum of necrotic cortical neurons (519 +/- 122 vs 952 +/- 130, mean +/- SE, P = 0.03, Kruskal-Wallis test) as well as contusion volume (0.50 +/- 0.14 vs 2.14 +/- 0.71 mm3, P = 0.004).(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in gene expression following traumatic brain injury in the rat

1. The relationship between immunoreactive inhibin and follicle-stimulating hormone (FSH) was studied in male and female chickens from hatch to sexual maturity. Plasma inhibin was estimated by a heterologous radioimmunoassay validated for use in the chicken. FSH was measured by a recently developed homologous radioimmunoassay. 2. In a cross-sectional study, blood samples and gonads were collected from chickens of both sexes at 1, 3, 5, 7, 14, 21 and 28 d after hatching and subsequently at 14-day intervals until 182 d of age. 3. In the female, plasma progesterone concentration (P4) progressively increased during sexual development. The plasma luteinising hormone (LH) concentration rose during the first week after hatching, and fluctuated thereafter, with troughs at 6 and 14 weeks and peaks at weeks 10 and 18. The plasma inhibin and FSH concentrations remained low until the start of puberty and increased simultaneously thereafter. However, from week 18 on, plasma inhibin continued to rise while plasma FSH fell. Hence, FSH and inhibin were positively correlated before puberty, but developed a negative correlation during sexual maturation. 4. In the male, plasma testosterone and LH concentrations increased 38- and 3.7-fold respectively over the period studied. Inhibin and FSH followed similar time courses and were consequently positively correlated. 5. These results suggest sex differences in the role of inhibin in regulating FSH secretion during development. The FSH-inhibin feedback loop may become operational at the onset of sexual maturity in the hens. In male chickens, the similar pattern of inhibin and FSH secretion suggests that inhibin secretion is driven by FSH.     

Caregiver burden at 6 months following severe traumatic brain injury

We compared the performance of three computer based classification methods when applied to the problem of detecting microaneurysms on digitised angiographic images of the retina. An automated image processing system segmented 'candidate' objects (microaneurysms or spurious objects), and produced a list of features on each candidate for use by the classifiers. We compared an empirically derived rule based system with two automated methods, linear discriminant analysis and a learning vector quantiser artificial neural network, to classify the objects as microaneurysms or otherwise. ROC analysis shows that the rule based system gave a higher performance than the other methods (p = 0.92) although a much greater development time is required.     

Expression of glucose transporters in rat brain following transient focal ischemic injury

To better understand genetic diversity of mammalian reoviruses, we studied sequence variability in the S3 gene segment of 17 field-isolate reovirus strains and prototype strains of the three reovirus serotypes. Strains studied were isolated over a 37-year period from different mammalian hosts and geographic locations. A high degree of variability was observed in the nucleotide sequences of the S3 gene, whereas the deduced amino acid sequences of the S3 gene product, sigma NS, were highly conserved. When variability among the S3 nucleotide sequences was analyzed using pairwise comparisons, we found that 5' and 3' noncoding regions were significantly more conserved than the remainder of the gene. This high degree of sequence conservation was also observed within the first 15 nucleotides of the 5' coding region. Phylogenetic analyses showed that multiple alleles of the S3 gene cocirculate and that genetic diversity in the S3 gene does not correlate with host species, geographic locale, or date of isolation. Phylogenetic trees constructed from variation in the S3 sequences are distinct from those previously generated from sequences that encode attachment protein sigma 1, core protein sigma 2, and outer capsid protein sigma 3, which supports the hypothesis that reovirus gene segments reassort in nature. These findings suggest that reovirus gene segments are well-adapted to mammalian hosts and that reovirus evolution has reached an equilibrium.     

Unilateral conditioning of an odor aversion in 6-day-old rat pups.

In young rats, several forms of olfactory memory can be functionally localized to one side of the brain by restricting training stimuli to one naris and corresponding olfactory bulb. In this experiment, the analysis of lateralized olfactory learning in 6-day-old rat pups was extended by an evaluation of the consequences of aversive reinforcers in a unilateral olfactory conditioning paradigm. An olfactory aversion was conditioned by delivering a mild footshock to animals in the presence of a novel odor. Olfactory stimulation was confined to one naris and corresponding olfactory bulb by inserting a soft rubber plug into the opposite naris. This lateralization in processing resulted in unilateral memory for the odor aversion that was only expressed when the trained naris was open during an odor preference test. The hypothesis that the hedonic value (or valence) component of conditioning is represented in structures that are unilaterally accessed during training and testing is discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Opposite trends of changes in reactive behaviours of macrophages and astrocytes following gamma-irradiation performed at different stages of prenatal development. A study in the injured brain of 6-day-old rat

Pregnant Wistar rats were exposed to a single 1.0 Gy dose of gamma rays on gestational days 13, 15, 17 or 19 (E13s, E15s, E17s and E19s, respectively). A mechanical injury was made in the cerebral hemisphere of their 6 day-old male offsprings. The injured rats were injected with [3H] thymidine on day 1 or 2 after injury and killed 4 h after the injection. Brain sections were processed for BSI-B4 isolectin histochemistry, subjected to autoradiography and examined microscopically to record numbers of proliferating and unproliferating macrophages located within the region of injury. The total number of macrophages as well as number of their divisions were minimal in E13s then showed a regular increase in E15s and E17s, and reached its maximal level in brains irradiated on E19. The trend of changes was opposite to that showed by changes in the intensity of astrocyte proliferation [Z. Setkowicz, K. Janeczko, Effects of prenatal gamma-irradiation on the astrocyte proliferation in response to injury in the brain of 6-day-old rat, Brain Res. 803 (1998) 122-128.]. The recruitment and proliferation of macrophages and the astrocyte proliferation were regarded as reactive processes occurring under control of different regulatory mechanisms acting within the region of injury.     

Effects of axonal injury on astrocyte proliferation and morphology in vitro: implications for astrogliosis

Mechanisms inducing gliosis following injury in the central nervous sy stem are poorly understood. We evaluated the effect of axonal injury on astrocyte and Schwann cell proliferation and morphology in vitro. Purified rat dorsal root ganglion neurons grown on monolayers of rat neonatal cortical astrocytes (N-ASneonatal cultures) or sciatic nerve-derived Schwann cells (N-SC cultures) were mechanically injured. Non-injured cultures served as controls. Cell proliferation near lesions was monitored by autoradiography 1,2,4, and 8 days postinjury. Axonal injury caused a significant transient increase in astrocyte proliferation immediately proximal and distal to the lesion. The lesion did not induce marked changes in the intensity of glial fibrillary acidic protein (GFAP) immunoreactivity. However, processes from GFAP-positive cells usually arranged in random fashion in noninjured cultures were aligned perpendicularly to the cut distal to lesions. Ultrastructural analysis in lesioned N-ASneonatal cultures indicated that proximal to the lesion filament-filled astrocytes were intermingled with axons. Distal to the lesion astrocyte processes formed layers, between which an increased amount of collagen-like material appeared with time postlesion. Axons distal to the lesion degenerated by 2 days, coinciding with the early disappearance of neurofilament immunoreactivity. In noninjured and proximally in injured N-SC cultures, Schwann cells extended processes, engulfing some axons. Distal to the lesion, Schwann cells appeared more rounded and neurites remained until 4 days postinjury. Media conditioned by injured or non-injured N-ASneonatal cultures did not affect neuron-induced Schwann cell proliferation. These findings demonstrate that axonal injury and degeneration cause a transient increase in astrocyte proliferation and induce morphological changes in astrocytes consistent with the onset of gliosis.     

Repeated isolation stress in the neonatal rat: Relation to brain dopamine systems in the 10-day-old rat.

Isolation of the rat pup from the nest and dam for one hour per day from PN 2–9 is a useful paradigm for producing stress in the neonate. These previously isolated rats respond to an amphetamine challenge with alterations in activity at the juvenile stage or as adults. Furthermore, when dopamine release is measured in the nucleus accumbens, juveniles release 3 times more dopamine after amphetamine than do controls. This study describes changes in behavior and brain dopamine systems at PN 10. Experiment 1 determined an appropriate amphetamine dose that could be used for behavioral activation at PN 10. Experiment 2 produced significant evidence of enhanced behavioral activation after the isolation paradigm and indicated that brain regions innervated by the mesolimbic dopamine system, septum, and hypothalamus display increased dopamine turnover and that the nigrostriatal pathway is less active. Likewise, in Experiment 3, in vivo microdialysis of the nucleus accumbens indicated that previously isolated pups respond to an amphetamine challenge with a several-fold increase in dopamine release over a 4-hour session. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Astrocytes are the major source of nerve growth factor upregulation following traumatic brain injury in the rat

A between-side comparison of GABAA receptor subunit expression levels in the globus pallidus and anterior-pole motor thalamic nuclei of rats with an ibotenate lesion of the striatum, and rats receiving a fetal striatal graft in the lesioned area was made by using immunocytochemistry with subunit-specific antibodies, at different times post-lesion or different times post-grafting. At 10 days post-lesion, there was already an increase in the labeling of the alpha 1- and beta 2/3-subunits in the globus pallidus, entopeduncular nucleus and ventrolateral nucleus ipsilateral to the lesion when compared with the contralateral side, while there were no significant changes at the level of the ventromedial nucleus. Labeling of the alpha 2-subunit showed a clear increase in the entopeduncular nucleus compared with the contralateral side at 10 days post-lesion. Similar changes were also observed for the different subunits studied at 30 and 120 days after lesioning. Rats with 20-day old transplants of fetal striatal neurons that were implanted in the ibotenate lesioned striatum at 10 days post-lesioning, continued to show changes in the expression of GABAA receptor subunits, albeit at a lower level than those of ibotenate lesioned rats at similar age post-lesion. However, when examining rats with 70-day old transplants, the ibotenate-lesion induced between-side changes were almost completely compensated. These findings suggest a correlation between the maturation of the grafts and their capability to function in reestablishing neuronal circuits as shown by the reduction of changes in GABAergic transmission induced by ibotenate lesions, as indicated by the reversal of changes in GABAA receptor subunit in several areas of the basal ganglia circuit.     

Up-regulation of type 2 iodothyronine deiodinase mRNA in reactive astrocytes following traumatic brain injury in the rat

Type 2 5'-deiodinase (5'-D2), which converts thyroxine to the more active thyroid hormone 3,5,3'-triiodothyronine (T3), is believed to be an important source of intracellular T3 in the brain. The activity of this enzyme is increased in hypothyroidism and decreased in hyperthyroidism, and as such, it serves an important role to protect the brain from wide fluctuations in T3 during changes in thyroidal state. Although it has been hypothesized that T3 may facilitate neuronal regeneration after CNS injury, the 5'-D2 response to brain injury is unknown. To assess the 5'-D2 mRNA response to injury, we performed in situ hybridization following traumatic brain injury. In unlesioned animals, 5'-D2 mRNA was undetectable. At 3 days posttrauma, 5'-D2 mRNA was detected in ipsilateral cortex near the contusion. A significant further increase of 5'-D2 mRNA was noted 7 days posttrauma in both hippocampus and cortex. Similar response was also observed on the contralateral side. Colocalization of 5'-D2 mRNA with glial fibrillary acidic protein indicates that reactive astrocytes were the major cellular source for the trauma-induced 5'-D2 expression. These data demonstrate, for the first time, a trauma-induced, astrocytic up-regulation of 5'-D2 mRNA, suggesting a potential role for T3 action in adult brain's response to injury and recovery.     

Executive functions and social competence in young children 6 months following traumatic brain injury.

Objective: This study examined the impact of traumatic brain injury (TBI) in young children on executive functions and social competence, and particularly on the role of executive functions as a predictor of social competence. Method: Data were drawn from a prospective, longitudinal study. Participants were children between the ages of 3 years 0 months and 6 years 11 months at time of injury. The initial sample included 23 with severe TBI, 64 with moderate TBI, and 119 with orthopedic injuries (OI). All participants were assessed at 3 and 6 months postinjury. Executive functions were assessed using neuropsychological tests (Delayed Alternation task and Shape School) and parent ratings on the Behavior Rating Inventory of Executive Function and Child Behavior Questionnaire. Parents rated children's social competence on the Adaptive Behavior Assessment System, Preschool and Kindergarten Behavior Scales, and Home and Community Social Behavior Scales. Results: Children with severe TBI displayed more negative outcomes than children with OI on neuropsychological tests, ratings of executive functions, and ratings of social competence (η2 ranged from .03 to .11). Neuropsychological tests of executive functions had significant but weak relationships with behavioral ratings of executive functions (ΔR2 ranged from .06 to .08). Behavioral ratings of executive functions were strongly related to social competence (ΔR2 ranged from .32 to .42), although shared rater and method variance likely contributed to these associations. Conclusions: Severe TBI in young children negatively impacts executive functions and social competence. Executive functions may be an important determinant of social competence following TBI. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Oxidative stress following traumatic brain injury in rats

BACKGROUND: Free radicals may be involved in the pathophysiology of traumatic brain injury (TBI) through oxidative damage of neurovascular structures. Endogenous antioxidants, such as ascorbate and alpha-tocopherol, may play a critical role in combating these oxidative reactions and their oxidized products can serve as an important index of oxidative stress. METHODS: We used electron spin resonance (ESR) spectroscopy and in vivo spin trapping (reaction of an organic compound with free radical species) to detect the possible generation of free radicals after TBI. Injury was inflicted by a weight drop technique over the head (5.7 kg-cm). Rats were intravenously infused with either 1 mL, 0.1 M of the spin trap, alpha-phenyl-N-tert-butyl nitrone (PBN), or an equivalent volume of saline immediately before TBI or sham-injury. Animals were divided into four groups: (1) Group I: PBN-infused sham-injured, (2) Group II: PBN-infused injured, (3) Group III: saline-infused sham-injured, and (4) Group IV: saline-infused injured. Additional groups of saline-infused uninjured, saline-infused, and PBN-infused injured animals were used for histopathology. Sixty minutes after TBI or sham-injury, rats were again anesthetized and decapitated. The brains were removed within 1 minute, homogenized, and extracted for lipids. The extracts were analyzed by ESR spectroscopy. Brain ascorbic acid (AA) concentration was determined spectrophotometrically, using the ascorbate oxidase assay. RESULTS: No PBN spin adduct signals (indicating trapped free radical species) were visible 60 minutes after TBI. All groups of rats showed an ascorbyl free radical signal. The ascorbyl signal intensity (AI) was, however, significantly higher in the injured rats, while the brain (AA) was significantly reduced. In addition, the ratio of AI/AA, which eliminates the effect of variable ascorbate concentrations in the brain, was also significantly higher in the injured animals. CONCLUSIONS: We conclude that 60 minutes following TBI there was a significantly increased level of oxidative stress in the brain. This may reflect formation of free radical species with subsequent interaction with ascorbate (antioxidant) during the 60 minute period. The lack of PBN spin adduct signals 1 hour after TBI may indicate that free radical generation is time dependent and might be detectable earlier or later than the 60 minute period.     

Lack of permanent nigrostriatal dopamine deficit following 6-hydroxydopamine injection into the rat striatum. Short communication

OBJECTIVE: Understanding the contributors to physical disability in older adults is an important component of the national health objective of expanding disability-free life by the year 2000. The purpose of this study was to determine the frequency with which older adults attribute their difficulty performing a number of common daily tasks to "old age" and to identify specific conditions and diseases associated with this attribution. Finally we sought to determine the characteristics that might differentiate persons able to attribute their disability to specific conditions from those who cite old age as the etiology of their disability. DESIGN: A cross-sectional, observational, study. SETTING: The Johns Hopkins Functional Status Laboratory. PARTICIPANTS: Two hundred thirty community-dwelling volunteers 60 years of age and older who could stand unassisted for > or = 1 minute and who were without cognitive impairment. MEASUREMENTS: A 1-day evaluation included physical performance evaluations, both performance-based and self-reported function for 27 tasks, and self-report of physician-diagnosed diseases. Those with difficulty in a task and those who denied difficulty but had changed the method of task performance (modification) because of an underlying health or physical condition were identified and asked to name the cause of their difficulty or task modification; options were specific diseases/medical conditions or "old age." The prevalence of "old age" citation as a cause of functional limitation, as well as its associated characteristics and medical conditions, was determined. MAIN RESULTS: Twenty percent of the 230 participants cited "old age" as the cause of their disability in two or more tasks. Tasks for which difficulty was most frequently attributed to "old age" were dressing oneself (31%), walking around the home (25%), walking 1/2 mile (5-6 blocks) (25%), cutting toenails (16%), getting in or out of a bed or chair or out a car (14% each), and ascending/descending stairs (13%). Significantly higher levels of arthritis, heart disease, and hearing loss were reported in persons attributing their disability to "old age" than in those not reporting "old age" as the cause of their disability. We found no differences in age, gender, race, education, or cognitive status for the two groups. However, individuals citing "old age" as the cause of functional decrements walked more slowly than those who cited a specific disease. CONCLUSIONS: These data suggest that a significant proportion of functional decline attributed to "aging" in older adults may be associated with specific conditions. Identifying and reducing the impact of these conditions may prove to be a useful approach to preventing or minimizing functional loss.     

Glucocorticoid receptor pathways are involved in the inhibition of astrocyte proliferation

In earlier studies, the neural cell adhesion molecule, N-CAM, was found to inhibit the proliferation of rat astrocytes both in vitro and in vivo. To identify the gene targets involved, we used subtractive hybridization to examine changes in gene expression that occur after astrocytes are exposed to N-CAM in vitro. While the mRNA levels for N-CAM decreased after such treatment, the levels of mRNAs for glutamine synthetase and calreticulin increased. Since glutamine synthetase and calreticulin are known to be involved in glucocorticoid receptor pathways, we tested a number of steroids for their effects on astrocyte proliferation. Dexamethasone, corticosterone, and aldosterone were all found to inhibit rat cortical astrocyte proliferation in culture in a dose-dependent manner. RU-486, a potent glucocorticoid antagonist, reversed the inhibitory effects of dexamethasone. These observations prompted the hypothesis that the inhibition of proliferation by N-CAM might be mediated through the glucocorticoid receptor pathway. Consistent with this hypothesis, the inhibition of astrocyte proliferation by N-CAM was reversed in part by a number of glucocorticoid antagonists, including RU-486, dehydroepiandrosterone, and progesterone. In transfection experiments with cultured astrocytes, N-CAM treatment increased the expression of a luciferase reporter gene under the control of a minimal promoter linked to a glucocorticoid response element. The enhanced activity of this construct stimulated by N-CAM was abolished in the presence of RU-486. The combined data suggest that astrocyte proliferation is in part regulated by alterations in glucocorticoid receptor pathways.     

Incidence of chronic pain following traumatic brain injury

OBJECTIVE: To index the frequency of reported chronic pain in patients with traumatic brain injury (TBI). DESIGN: A case series study was conducted on consecutive patients with TBI. SETTING: TBI patients were recruited from an adult tertiary care center brain injury clinic. PATIENTS: A consecutive sample of 132 patients who attended a brain injury rehabilitation center after TBI. The sample included 53 mild and 79 moderate/severe TBI patients. OUTCOME MEASURES: Patients were administered a protocol that indexed pain site, frequency, severity, and duration. RESULTS: Chronic pain was reported by 58% of mild TBI and 52% of moderate/severe TBI patients. Headaches were the most commonly reported pain problem. Chronic headaches were reported by 47% of mild TBI patients and 34% of moderate/ severe TBI patients. Neck/shoulder, back, upper limb, and lower limb pain were reported similarly by mild and moderate/severe TBI patients. CONCLUSIONS: Findings indicate that chronic pain is a significant problem in mild and moderate/severe TBI patients. More effective diagnosis of TBI patients with chronic pain may facilitate rehabilitation of these patients.     

Simvastatin inhibits myointimal hyperplasia following carotid artery injury in cholesterol-fed rabbits

The effect of simvastatin, a potent inhibitor of 3-hydroxy 3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) was evaluated in an experimental model of myointimal hyperplasia in cholesterol-fed rabbits. Myointimal hyperplasia was induced by an air-drying injury of the left carotid artery followed by a 2%-cholesterol diet for 14 days. A 2-week oral treatment with simvastatin (6 mg/kg/day, p.o.) significantly lowered the circulating levels of cholesterol and triglycerides (41% and 49% inhibition respectively) as well as the low density lipoprotein (LDL)-cholesterol and high density lipoprotein (HDL)-cholesterol levels. Simvastatin also strongly affected the uptake of cholesterol in the arteries occurring as a consequence of vascular injury (44% inhibition, P < 0.001). Morphometric analysis revealed that both the intima and the media areas increased substantially 2 weeks after the lesion and showed a considerable smooth muscle cell accumulation in the neointima together with the presence of numerous foam cells. A 16-day oral treatment with simvastatin strongly reduced smooth muscle cells hyperplasia occurring in both the media and the intima following deendothelialization (19% and 60% inhibition respectively) suggesting that simvastatin may be a useful inhibitor of restenosis which occurs following vascular injury.