Biomedical subjects

I M Macrae

Publications and source records attributed to I M Macrae.

At least 19 recordsLinked to original sources

PubMed2006

Identification of the growth arrest and DNA damage protein GADD34 in the normal human heart and demonstration of alterations in expression following myocardial ischaemia.

Growth arrest and DNA damage protein 34 (GADD34) is a multifunctional protein upregulated in response to cellular stress and is believed to mediate DNA repair and restore protein synthesis. In the present study we have examined GADD34 immunoreactivity in human myocardial tissue at defined survival times following cardiac arrest and determined alterations in expression following ischaemia. In the normal human heart, GADD34 immunoreactivity was generally intense and present within most cells. GADD34 immunoreactivity was downregulated in tissue displaying ischaemic damage and remained intense in adjacent non-infarcted tissue. Unlike brain, GADD34 was not found to be upregulated in the peri-infarct zone. Cells displaying apoptotic changes were located in regions displaying reduced GADD34 immunoreactivity. In the brain, it is thought that GADD34 supports re-initiation of protein synthesis following ischaemia. Similarly, GADD34 may perform important functions in cardiac tissue in response to ischaemia.

Antigens, Differentiation↗

PubMed2006

Oestrogen and stroke: the potential for harm as well as benefit.

Epidemiological studies point to a beneficial influence of the female reproductive hormones on stroke risk in that women have a lower incidence of stroke prior to the menopause compared with men, but this difference weakens with age and stroke risk in women rises after the menopause. However, recent Women's Health Initiative trials in post-menopausal women report an increased stroke risk on hormone replacement therapy. An influence of gender is also apparent on stroke outcome in animal models: female rats exposed to transient MCA (middle cerebral artery) occlusion sustain less brain damage than age-matched males, with loss of protection following ovariectomy. The major hormone thought to be responsible for beneficial influences on stroke incidence and outcome is oestrogen, and a large preclinical literature now exists where exogenously administered oestrogen has been studied in male and ovariectomized female rats using a range of stroke models and outcome measures. Most of these studies administer oestrogen prior to the stroke, use a model of transient ischaemia followed by reperfusion and report a significant oestrogen-induced neuroprotection. However, in some studies where the MCA is permanently occluded, oestrogen pre-treatment in ovariectomized female rats has been shown to significantly exacerbate ischaemic damage. Therefore preclinical results demonstrate harmful as well as beneficial influences of oestrogen on the ischaemic brain, highlighting the need for further study to elucidate the mechanisms responsible for both detrimental and beneficial influences. Ultimately, this could lead to the development of new classes of oestrogenic compounds with improved risk/benefit profiles, designed to selectively activate pathways inducing only the beneficial effects of oestrogen in vivo.

Animals↗

PubMed2005

Brain aromatase expression after experimental stroke: topography and time course.

Brain aromatase has been shown to be increased in expression after neurotoxic damage and to exert neuroprotection via generation of local oestrogens. The present study investigates the topography and time course of brain aromatase expression after experimental stroke (middle cerebral artery occlusion (MCAO)). Ovariectomised stroke prone spontaneously hypertensive rats underwent distal MCAO by electrocoagulation. Immunohistochemistry revealed increased brain aromatase expression at 24h and 8 days in the cortical penumbra/peri-infarct zones with no increase evident at 2h or 30 days post-MCAO. Double label studies indicate that some of the increased aromatase expression is associated with astrocytic processes. Thus, this is the first evidence that aromatase protein is increased after MCAO and the location (peri-infarct), time course (within 24h) and cellular localisation (astrocytic) indicate the potential for aromatase to promote the survival of cells in the penumbra after experimental stroke by local synthesis of oestrogens.

Animals↗

PubMed2004

Impaired functional recovery after stroke in the stroke-prone spontaneously hypertensive rat.

BACKGROUND AND PURPOSE: To identify if the stroke-prone spontaneously hypertensive rat (SHRSP) exhibits impaired functional recovery after stroke compared with its normotensive reference strain, the Wistar Kyoto rat (WKY). METHODS: In study 1, a 2-mm distal middle cerebral artery occlusion (middle cerebral artery occlusion) was performed in both strains and recovery assessed using a 33-point neurological score. Because SHRSPs displayed much larger infarcts than WKYs, study 2 and study 3 involved extending the length of middle cerebral artery (MCA) occlusion in the WKY to increase the volume and distribution of infarction to comparable levels with SHRSP. Animals were assessed with the neurological score, tapered beam walk, and cylinder tests. RESULTS: In study 1, infarct volume (expressed as a percent of contralateral hemisphere) was WKY 13.1+/-3% and SHRSP 19.8+/-1%. Initial neurological deficit was greater (WKY 25+/-1, SHRSP 22+/-1, out of a possible 33) and subsequent recovery was poorer in SHRSP. In studies 2 and 3, infarct volume and distribution (study 2, WKY 21.8+/-1.3%, SHRSP 22.9+/-3%; study 3, WKY 17.2+/-2%, SHRSP 16.5+/-3%) and initial neurological deficit at 2 hours after middle cerebral artery occlusion (study 2 WKY 23+/-1, SHRSP 22+/-2; study 3 WKY 25+/-1 and SHRSP 23+/-1; mean+/-SEM) were comparable between strains. However, whereas WKY recovered toward normal scores, SHRSP scored significantly lower 2 weeks (study 2) and 4 weeks (study 3) after middle cerebral artery occlusion. Beam walk data revealed long-term impairment in SHRSP contralateral limb use, compared with WKY, at days 3, 7, and 28 (P<0.05). CONCLUSIONS: SHRSP exhibit impaired functional recovery after stroke compared with WKY.

Animals↗

PubMed2004

Neuroprotection by a selective estrogen receptor beta agonist in a mouse model of global ischemia.

The present study employs selective estrogen receptor (ER) agonists to determine whether 17beta-estradiol-induced neuroprotection in global ischemia is receptor mediated and, if so, which subtype of receptor (ERalpha or ERbeta) is predominantly responsible. Halothane-anesthetized female C57Bl/6J mice were ovariectomized, and osmotic minipumps containing ERbeta agonist diarylpropiolnitrile (DPN) (8 mg.kg(-1).day(-1), n = 12) or vehicle (50% DMSO in 0.9% saline) (n = 9) or ERalpha agonist propyl pyrazole triol (PPT) (2 mg.kg(-1).day(-1), n = 13) or vehicle (50% DMSO in 0.9% saline) (n = 10) were implanted subcutaneously. One week later transient global ischemia was induced by bilateral carotid artery occlusion under halothane anesthesia, and the mice were perfusion fixed 72 h later. ERbeta agonist DPN significantly reduced ischemic damage by 70% in the caudate nucleus and 55% in the CA1 region compared with vehicle controls (P < 0.05, Mann-Whitney U-statistic). In contrast, pretreatment with the ERalpha agonist PPT had no effect on the extent of neuronal damage compared with controls. The data indicate a significant estrogen receptor-mediated neuroprotection in a global cerebral ischemia model involving ERbeta.

Animals↗

PubMed2004

Up-regulation of a growth arrest and DNA damage protein (GADD34) in the ischaemic human brain: implications for protein synthesis regulation and DNA repair.

GADD34 is a growth arrest and DNA damage inducible gene up-regulated in response to DNA damage, cell cycle arrest and apoptosis. It is thought that GADD34 may play a crucial role in cell survival in ischaemia. GADD34 expression was assessed immunohistochemically in post-mortem human hippocampal tissue obtained from patients surviving for defined periods (0-24 h; 24 h-7 days) after a cardiac arrest and in age-matched control subjects. In control brain, cytoplasm staining in GADD34 immunopositive cells was faint but present throughout the hippocampus and cortex. There was minimal change in GADD34 expression in the group surviving 0-24 h after cardiac arrest. However GADD34 immunostaining was markedly increased in selectively vulnerable regions in the 24 h-7 day survival group. Increased GADD34 staining was present in ischaemic neurones and in some morphologically normal neurones after cardiac arrest. Extensive ischaemic damage was found to correlate with elevated GADD34 immunostaining in the CA1 layer of the hippocampus (**P < 0.0016). In addition, GADD34 was found to colocalize with proliferating cell nuclear antigen in some neurones. The up-regulation of GADD34 in response to global ischaemia in the human brain plus its influence on protein synthesis and DNA repair suggests that this protein may have the potential to influence cell survival.

Adolescent↗

PubMed2002

Specific expression of the cell cycle regulation proteins, GADD34 and PCNA, in the peri-infarct zone after focal cerebral ischaemia in the rat.

Cell cycle proteins play key roles in cell survival or death under pathological conditions. Expression of growth arrest and DNA damage-inducible protein, GADD34 and proliferating cell nuclear antigen (PCNA) have been investigated in the core and peri-infarct zone at 2 and 24 h after middle cerebral artery occlusion (MCAO). At these times after MCAO, numerous GADD34-positive cells were present, particularly in the peri-infarct zone (e.g. 24 +/- 4 and 52 +/- 6 immunopositive cells/0.25 mm2 at 2 and 24 h, respectively, in cortex). PCNA-immunopositive cells were barely detectable in the peri-infarct zone at 2 h; however, numerous PCNA-immunopositive cells were present in this zone by 24 h (0.7 +/- 0.3 and 10.6 +/- 1.5 immunopositive cells/0.25 mm2, respectively) as well as in the adjacent cortex and in the contralateral cingulate cortex. Most GADD34-immunopositive cells coexpressed the neuronal marker Neu-N with a smaller number coexpressing the microglial marker, Mrf-1. Evidence of morphologically 'abnormal' and 'normal' GADD34 immunopositive neurons was found within the peri-infarct zone. The majority of PCNA immunopositive cells were Mrf-1 positive with a smaller number Neu-N positive. Double-labelling revealed colocalization of GADD34 and PCNA in some cells within the peri-infarct zone and in the ependymal cells lining the ventricles. The presence of GADD34 and PCNA in a key anatomical location pertinent to the evolving ischaemic lesion indicates that GADD34, either alone or in combination with PCNA, has the potential to influence cell survival in ischaemically compromised tissue.

Animals↗

PubMed2001

Reciprocal consomic strains to evaluate y chromosome effects.

We have previously demonstrated that the SHRSP Y chromosome contains a locus that contributes to hypertension in SHRSP/WKY F2 hybrids and that SHRSP exhibit an increased vulnerability to focal cerebral ischemia after permanent middle cerebral artery occlusion (MCAO). This increased vulnerability is inherited as a codominant trait, and a putative role for the Y chromosome has been suggested in F1 hybrids. The objective of this study was to investigate further the role of Y chromosome in blood pressure (BP) regulation and in the vulnerability to cerebral ischemia. We have constructed consomic strains by selectively replacing the Y chromosome from WKY rats with that of SHRSP, and vice versa, by using a marker-assisted breeding strategy. Permanent MCAO was carried out by electrocoagulation, with infarct volume expressed as a percentage of the ipsilateral hemisphere. Systolic blood pressure was measured by radiotelemetry during a baseline period of 5 weeks followed by a 3-week period of salt loading. We observed that the transfer of the Y chromosome from WKY onto SHRSP background significantly reduced systolic BP in consomic strains, SP.WKYGlaY(w) (n=6) versus SHRSP (n=6) (209.2+/-10.4 mm Hg versus 241.7+/-7.7 mm Hg, F=5.88, P=0.038) during the salt-loading period. In the reciprocal consomic strain, WKY.SPGlaY(s) (n=5), systolic BP was increased compared with WKY parental strain (n=6) (147.6+/-2.4 mm Hg versus 132.6+/-5.1 mm Hg, F=6.11, P=0.035) during baseline. Infarct volumes in consomic strains were not significantly different from their respective parental strain: WKY.SPGlaY(s) (n=7) versus WKY (n=7), 22.8+/-3.7% versus 22.2+/-8.0%, 95% CI=-12.7, 4.2, P=0.3; SP.WKYGlaY(w) (n=7) versus SHRSP (n=6), 37.7+/-4.4% versus 33.6+/-7.6%, 95% CI=-20.3, 12.1, P=0.5. We conclude that the SHRSP Y chromosome harbors a locus contributing to systolic BP, whereas no contribution to vulnerability to cerebral ischemia can be detected.

Animals↗

PubMed2001

Characterization of the microglial response to cerebral ischemia in the stroke-prone spontaneously hypertensive rat.

Stroke-prone spontaneously hypertensive rats (SHRSP) sustain more ischemic damage after middle cerebral artery occlusion than do their reference strain, the Wistar-Kyoto rat (WKY). The cause of increased stroke sensitivity is still under investigation. In general, SHRSP display a greater response to inflammatory stimuli than do WKY. Because inflammatory cells may influence the extent of damage in experimental stroke, this study has investigated the acute inflammatory response to focal ischemia in SHRSP and WKY. Adult male SHRSP (n=5) and WKY (n=5) were anesthetized and underwent distal middle cerebral artery occlusion. After 24 hours of recovery, infarct volume, neutrophil counts, and activated microglia counts were performed. SHRSP displayed more ischemic damage than did WKY (135+/-4.7 versus 102+/-4.7 mm(3) [mean+/-SEM], P<0.005). Brain neutrophil counts were extremely low in both strains. SHRSP displayed significantly more activated microglia than did WKY in the ipsilateral hemisphere (respective SHRSP versus WKY values [mean+/-SEM] were 88+/-3.6 versus 51+/-3.4 per mm(2) for the cortical peri-infarct region [P<0.005] and 183+/-7.9 versus 156+/-3.7 per mm(2) for the infarct core [P<0.05]) and in the contralateral hemisphere (eg, respective SHRSP versus WKY values were 102+/-3.2 versus 50+/-3.1 per mm(2) for the sensorimotor cortex [P<0.0001]). No neutrophils and very few activated microglia were found within the brains of naive rats. However naive SHRSP possessed more microglia (resting and activated) than did naive WKY. This study demonstrates a more pronounced microglial response to focal ischemia in SHRSP compared with WKY and provides evidence of a potential role for inflammatory processes in response to ischemic damage.

Animals↗

PubMed2001

Ebselen protects both gray and white matter in a rodent model of focal cerebral ischemia.

BACKGROUND AND PURPOSE: The neuroprotective efficacy of an intravenous formulation of the antioxidant ebselen has been comprehensively assessed with specific regard to conventional quantitative histopathology, subcortical axonal damage, neurological deficit, and principal mechanism of action. METHODS: Transient focal ischemia (2 hours of intraluminal thread-induced ischemia with 22 hours of reperfusion) was induced in the rat. Ebselen (1 mg/kg bolus plus 1 mg/kg per hour IV) or vehicle was administered at the start of reperfusion and continued to 24 hours. Neurological deficit was assessed 24 hours after ischemia. Gray matter damage was evaluated by quantitative histopathology. Axonal damage was determined with amyloid precursor protein immunohistochemistry used as a marker of disrupted axonal flow and Tau-1 immunohistochemistry to identify oligodendrocyte pathology. Oxidative damage was determined by 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 4-hydroxynonenal (4-HNE) immunohistochemistry. RESULTS: Ebselen significantly reduced the volume of gray matter damage in the cerebral hemisphere (by 53.6% compared with vehicle, P<0.02). Axonal damage was reduced by 46.8% (P<0.002) and the volume of oligodendrocyte pathology was reduced by 60.9% (P<0.005). The neurological deficit score was reduced by 40.7% (P<0.05) and the volume of tissue immunopositive for 8-OHdG and 4-HNE was reduced by 65% (P<0.002) and 66% (P<0.001), respectively, in ebselen-treated animals. CONCLUSIONS: Delayed (2-hour) treatment with intravenous ebselen significantly reduced gray and white matter damage and neurological deficit associated with transient ischemia. The reduction in tissue displaying evidence of oxidative stress suggests that the major mechanism of action is attenuation of free radical damage.

Animals↗

PubMed2000

Impaired cerebral autoregulation 24 h after induction of transient unilateral focal ischaemia in the rat.

Cerebral blood flow (CBF) and cerebral autoregulation have been investigated 24 h after transient focal ischaemia in the rat. Cerebral blood flow was measured autoradiographically before and during a moderate hypotensive challenge, to test autoregulatory responses, using two CBF tracers, (99m)Tc-d,l-hexamethylproyleneamine oxide and 14C-iodoantipyrine. Prior to induced hypotension, CBF was significantly reduced within areas of infarction; cortex (28 +/- 20 compared with 109 +/- 23 mL/100 g/min contralateral to ischaemic focus, P = 0.001) and caudate (57 +/- 31 compared with 141 +/- 32 mL/100 g/min contralaterally, P = 0.005). The hypotensive challenge (mean arterial pressure reduced to 60 mmHg by increasing halothane concentration) did not compromise grey matter autoregulation in the contralateral hemisphere; CBF data were not significantly different at normotension and during hypotension. However, in the ipsilateral hemisphere, a significant volume of cortex adjacent to the infarct, which exhibited normal flow at normotension, became oligaemic during the hypotensive challenge (e.g. frontal parietal cortex 109 +/- 15% to 65 +/- 15% of cerebellar flow, P < 0.01). This resulted in a 2.5-fold increase in the volume of cortex which fell below 50% cerebellar flow (39 +/- 34 to 97 +/- 46 mm3, P = 0.003). Moderate hypotension induced a significant reduction in CBF in both ipsilateral and contralateral subcortical white matter (P < 0.01). In peri-infarct caudate tissue, CBF was not significantly affected by hypotension. In conclusion, a significant volume of histologically normal cortex within the middle cerebral artery territory was found to have essentially normal levels of CBF but impaired autoregulatory function at 24 h post-ischaemia.

Animals↗

PubMed2000

Estrogen as a neuroprotectant in stroke.

Recent evidence suggests that reproductive steroids are important players in shaping stroke outcome and cerebrovascular pathophysiologic features. Although women are at lower risk for stroke than men, this native protection is lost in the postmenopausal years. Therefore, aging women sustain a large burden for stroke, contrary to a popular misconception that cancer is the main killer of women. Further, the value of hormone replacement therapy in stroke prevention or in improving outcome remains controversial. Estrogen has been the best studied of the sex steroids in both laboratory and clinical settings and is considered increasingly to be an endogenous neuroprotective agent. A growing number of studies demonstrate that exogenous estradiol reduces tissue damage resulting from experimental ischemic stroke in both sexes. This new concept suggests that dissecting interactions between estrogen and cerebral ischemia will yield novel insights into generalized cellular mechanisms of injury. Less is known about estrogen's undesirable effects in brain, for example, the potential for increasing seizure susceptibility and migraine. This review summarizes gender-specific aspects of clinical and experimental stroke and results of estrogen treatment on outcome in animal models of cerebral ischemia, and briefly discusses potential vascular and parenchymal mechanisms by which estrogen salvages brain.

Animals↗

PubMed2000

Investigation of estrogen status and increased stroke sensitivity on cerebral blood flow after a focal ischemic insult.

Recently the authors have shown that female stroke-prone spontaneously hypertensive rats (SHRSPs) in proestrus (high endogenous estrogen), sustain more than 20% smaller infarcts after middle cerebral artery occlusion (MCAO) compared with SHRSPs in metestrus (low endogenous estrogen). Because estrogen has vasodilator properties, the authors investigated whether the estrous state influences cerebral blood flow (CBF) after MCAO. CBF was measured 2.5 hours after a distal MCAO by [14C]iodo-antipyrine autoradiography in conscious SHRSPs either in metestrus or in proestrus. There were no significant differences in CBF when analyzed either at predetermined anatomic regions or by cumulative distribution analysis of areas with flow <25 mL/100 g/min. As a positive internal control, the authors compared results in SHRSPs with those in their normotensive reference strain, Wistar Kyoto rat. SHRSPs displayed more severe and widespread ischemia than Wistar Kyoto rats. Thus, the absence of demonstrable CBF differences between estrous states appears to be unrelated to the CBF measurement paradigm. In conclusion, the smaller infarct size afforded in proestrus in SHRSPs is unlikely to be due to an influence on CBF.

Animals↗

PubMed2000

Estrogen status affects sensitivity to focal cerebral ischemia in stroke-prone spontaneously hypertensive rats.

Estrogen treatment has been shown to reduce ischemic brain damage. Because endogenous estrogen levels fluctuate markedly during the estrous cycle, we investigated the effect of stage of estrous cycle on ischemic brain damage. Halothane anesthetized 3- to 5-mo-old female Wistar-Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) in proestrus (high estradiol levels) or metestrus (low estradiol levels) underwent permanent middle cerebral artery occlusion. In SHRSP, infarct volume at 24 h postocclusion was 24% smaller in proestrus compared with metestrus [208.6 +/- 9.5 mm(3) (n = 7) vs. 272.7 +/- 23.8 mm(3) (n = 7), respectively, means +/- SE; P = 0.0278, unpaired t-test]. In WKY, infarct volumes were similar in proestrus and metestrus [157.0 +/- 5.4 mm(3) (n = 5) and 131.5 +/- 16.5 mm(3) (n = 8), respectively; P = not significant (NS)]. Brain swelling (ipsilateral minus contralateral hemispheric volumes) was similar in proestrus and metestrus for SHRSP [138 +/- 9 mm(3) (n = 6) and 136 +/- 10 mm(3) (n = 7), respectively] and for WKY [103 +/- 15 mm(3) (n = 5) and 90 +/- 11 mm(3) (n = 8), respectively]. Thus the reduction in infarct size in SHRSP is caused by a true attenuation of the infarct volume and not simply by a reduction in brain edema.

Animals↗

PubMed1999

Genes encoding atrial and brain natriuretic peptides as candidates for sensitivity to brain ischemia in stroke-prone hypertensive rats.

-Previous studies suggested that atrial natriuretic peptide gene (Anp) and brain natriuretic peptide gene (Bnp) are plausible candidate genes for susceptibility to stroke and for sensitivity to brain ischemia in the stroke-prone spontaneously hypertensive rat (SHRSP). We performed structural and functional analyses of these 2 genes in SHRSP from Glasgow colonies (SHRSPGla) and Wistar-Kyoto rats from Glasgow colonies (WKYGla) and developed a radiation hybrid map of the relevant region of rat chromosome 5. Sequencing of the coding regions of the Anp and Bnp genes revealed no difference between the 2 strains. Expression studies in brain tissue showed no differences at baseline and at 24 hours after middle cerebral artery occlusion. Plasma concentrations of atrial natriuretic peptide (ANP) did not differ between the SHRSPGla and WKYGla, whereas concentrations of brain natriuretic peptide were significantly higher in the SHRSPGla as compared with the WKYGla (n=11 to 14; 163+/-21 pg/mL and 78+/-14 pg/mL; 95% confidence interval 31 to 138, P=0.003). We did not detect any attenuation of endothelium-dependent relaxations to bradykinin or ANP in middle cerebral arteries from the SHRSPGla; indeed the sensitivity to ANP was significantly increased in arteries harvested from this strain (WKYGla: n=8; pD2=7. 3+/-0.2 and SHRSPGla: n=8; pD2=8.2+/-0.15; P<0.01). Moreover, radiation hybrid mapping and fluorescence in situ hybridization allowed us to map the Anf marker in the telomeric position of rat chromosome 5 in close proximity to D5Rat48, D5Rat47, D5Mgh15, and D5Mgh16. These results exclude Anp and Bnp as candidate genes for the sensitivity to brain ischemia and pave the way to further congenic and physical mapping strategies.

Amino Acid Substitution↗

PubMed1999

Genetic and gender influences on sensitivity to focal cerebral ischemia in the stroke-prone spontaneously hypertensive rat.

We have investigated genetic transmission of increased sensitivity to focal cerebral ischemia and the influence of gender in the stroke-prone spontaneously hypertensive rat (SHRSP). Halothane-anesthetized, 3- to 5-month-old male and female Wistar-Kyoto rats (WKY), SHRSP, and the first filial generation rats (F1 crosses 1 and 2) underwent distal (2 mm) permanent middle cerebral artery occlusion (MCAO) by electrocoagulation. Infarct volume was measured by using hematoxylin-eosin-stained sections and image analysis 24 hours after ischemia and expressed as a percentage of the volume of the ipsilateral hemisphere. Infarct volume in males and females grouped together were significantly larger in SHRSP, F1 cross 1 (SHRSP father), and F1 cross 2 (WKY father), at 36.6+/-2.3% (mean+/-SEM, P<0.001, n=15), 25.4+/-2.4% (P<0.01, n=14), and 33. 9+/-1.6% (P<0.001, n=18), respectively, compared with WKY (14+/-2%, n=17). Male F1 cross 1 (18.9+/-2.4%, n=6) developed significantly smaller infarcts than male F1 cross 2 (32.8+/-2%, n=8, P<0.005). Females, which underwent ischemia during metestrus, developed larger infarcts than respective males. A group of females in which the cycle was not controlled for developed significantly smaller infarcts than females in metestrus. Thus, the increased sensitivity to MCAO in SHRSP is retained in both F1 cross 1 and cross 2 hybrids, suggesting a dominant or codominant trait; response to cerebral ischemia appears to be affected by gender and stage in the estrous cycle. In addition, the male progenitor of the cross (ie, SHRSP versus WKY) influences stroke sensitivity in male F1 cohorts.

Animals↗

PubMed1998

Susceptibility to cerebral infarction in the stroke-prone spontaneously hypertensive rat is inherited as a dominant trait.

BACKGROUND AND PURPOSE: Susceptibility to cerebral infarction was compared in stroke-prone spontaneously hypertensive (SHRSP), normotensive Wistar-Kyoto (WKY) rats, and F1 hybrids derived from a SHRSP/WKY cross. METHODS: The proximal left middle cerebral artery (MCA) was occluded under anesthesia and infarct volume assessed 24 hours later by magnetic resonance imaging and confirmed 5 days later by quantitative histopathology. Total hemispheric infarct volume was expressed as a percentage of the total brain volume. RESULTS: Infarct volumes measured by MRI in adult SHRSP (19.5 +/- 2.0%) and F1 hybrid rats (19.4 +/- 1.9%) were significantly greater than in WKY (11.1 +/- 2.4; CI [6.07, 10.76]) and (5.93, 10.52), respectively, P<.001). Sensitivity to an ischemic insult was unrelated to blood pressure: although systolic blood pressures differed between young versus adult male SHRSP and between female versus male SHRSP and F1 hybrids, infarct volumes were equal. A close correlation was found between infarct volumes measured by MRI and histology (r=.92, P<.0001). CONCLUSIONS: Outcome to MCA occlusion (MCAO) measured with MRI provides a reproducible and nonterminal quantitative phenotypic marker of stroke susceptibility in the SHRSP. This is the first study to employ MCAO with MRI to quantify stroke susceptibility in F1 hybrid rats and indicates a dominant mode of inheritance for this phenotype.

Animals↗

PubMed1997

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

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

Aminoisobutyric Acids↗