Hyperglycemia accelerates apparent diffusion coefficient-defined lesion growth after focal cerebral ischemia in rats with and without features of metabolic syndrome.

Poststroke hyperglycemia is associated with a poor outcome yet clinical management is inadequately informed. We sought to determine whether clinically relevant levels of hyperglycemia exert detrimental effects on the early evolution of focal ischemic brain damage, as determined by magnetic resonance imaging, in normal rats and in those modeling the 'metabolic syndrome'. Wistar Kyoto (WKY) or fructose-fed spontaneously hypertensive stroke-prone (ffSHRSP) rats were randomly allocated to groups for glucose or vehicle administration before permanent middle cerebral artery occlusion. Diffusion-weighted imaging was carried out over the first 4 hours after middle cerebral artery occlusion and lesion volume calculated from apparent diffusion coefficient maps. Infarct volume and immunostaining for markers of oxidative stress were measured in the fixed brain sections at 24 hours. Hyperglycemia rapidly exacerbated early ischemic damage in both WKY and ffSHRSP rats but increased infarct volume only in WKY rats. There was only limited evidence of oxidative stress in hyperglycemic animals. Acute hyperglycemia, at clinically relevant levels, exacerbates early ischemic damage in both normal and metabolic syndrome rats. Management of hyperglycemia may have greatest benefit when performed in the acute phase after stroke in the absence or presence of comorbidities.

An MRI-histological study of white matter in stroke-free SHRSP.

Hypertension is associated with cerebral small vessel disease (SVD) and with diffuse white matter hyperintensities (WMH) on T2-weighted magnetic resonance imaging (MRI). We tested whether stroke-prone spontaneously hypertensive rats (SHRSP), a model of chronic hypertension, exhibit WMH. Male SHRSP (age 10 months) without stroke symptoms were compared with age-matched male WKY rats. Stroke-prone spontaneously hypertensive rats exhibited no WMH on MRI scans (T2, T2*, diffusion tensor imaging) and no neuropathological lesions. While leptomeningeal arteries exhibited fibrohyaline wall thickening, with decreased smooth muscle actin relative to WKY, deep penetrating arterioles within the caudate nuclei had no vasculopathy. We conclude that WMH are not an obligate feature of stroke-free SHRSP aged up to 10 months.

The design of a double-tuned two-port surface resonator and its application to in vivo hydrogen- and sodium-MRI.

The design and construction of a two-port surface transceiver resonator for both (1)H-and (23)Na-MRI in the rodent brain at 7 T is described. Double-tuned resonators are required for accurately co-registering multi-nuclei data sets, especially when the time courses of (1)H and (23)Na signals are of interest as, for instance, when investigating the pathological progression of ischaemic stroke tissue in vivo. In the current study, a single-element two-port surface resonator was developed wherein both frequency components were measured with the same detector element but with each frequency signal routed along different output channels. This was achieved by using the null spot technique, allowing for optimal variable tuning and matching of each channel in situ within the MRI scanner. The (23)Na signal to noise ratio, measured in the ventricles of the rat brain, was increased by a factor of four compared to recent state-of-the-art rat brain studies reported in the literature. The resonator's performance was demonstrated in an in vivo rodent stroke model, where regional variations in (1)H apparent diffusion coefficient maps and the (23)Na signal were recorded in an interleaved fashion as a function of time in the acute phase of the stroke without having to exchange, re-adjust, or re-connect resonators between scans. Using the practical construction steps described in this paper, this coil design can be easily adapted for MRI of other X-nuclei, such as (17)O, (13)C, (39)K, and (43)Ca at various field strengths.

Evolution of GADD34 expression after focal cerebral ischaemia.

GADD34, a stress response protein associated with cell rescue, DNA repair and apoptosis, is expressed in the ischaemic brain. The C-terminal region of GADD34 has homology with the Herpes Simplex Virus protein, ICP34.5, which overcomes the protein synthesis block after viral infection by actively dephosphorylating eukaryotic translation initiation factor 2alpha (eIF2alpha). The carboxy terminus of GADD34 is also capable of dephosphorylating eIF2alpha and therefore has the capacity to restore the protein synthesis shutoff associated with ischaemia. This study examines the distribution and time course of GADD34 expression after focal cerebral ischaemia. Focal ischaemia or sham procedure was carried out on Sprague-Dawley rats with survival times of 4, 12, 24 h, 7 and 30 days. Brains were processed for histology and immunohistochemistry. Ischaemic damage was mapped onto line diagrams and GADD34 positive cells counted in selected regions of cortex and caudate. GADD34 immunopositive cells (mainly neurones), expressed as cells/mm2, were present in ischaemic brains at 4 h (e.g., peri-infarct cortex 20 +/- 5; contralateral cortex 3 +/- 1, P < 0.05). Of the time points examined, numbers of GADD34 positive cells were highest 24 h after ischaemia (peri-infarct cortex 31 +/- 7.3, contralateral cortex 0.1 +/- 0.1, P < 0.05). Immunopositive cells, following a similar time course, were identified within the peri-infarct zone in the caudate nucleus and in ipsilateral cingulate cortex (possibly as a consequence of cortical spreading depression). GADD34 positive cells did not co-localise with a marker of irreversible cell death (TUNEL). Taken together, GADD34 positive cells in key neuroanatomical locations pertinent to the evolving ischaemic lesion, the lack of co-localisation with TUNEL and the protein's known effects on restoring protein synthesis, repairing DNA and involvement in ischaemic pre-conditioning suggests that it has the potential to influence cell survival in ischaemically compromised tissue.

New models of focal cerebral ischaemia.

1. Studies in animal models of stroke have provided an invaluable contribution to our current understanding of the pathogenesis of cerebral ischaemia. The strengths of stroke research in animals are: 1) the ability to control the severity, duration, location and cause of the ischaemia, variables which confound interpretation of human stroke data; 2) co-existent disease states and variations in cerebrovascular anatomy are avoided; and 3) physiological parameters such as blood pressure, blood gases, temperature and plasma glucose (all of which influence the magnitude of the ischaemic lesion) can be closely monitored and controlled. Taking all these things on board, it is possible to induce a consistent focal ischaemic lesion in animal models of stroke (e.g. the permanent occlusion of the middle cerebral artery (MCA) in the rat). This has resulted in the wide use of animal models for assessment of anti-ischaemic drug efficacy as well as for research into the pathophysiological sequelae of stroke. 2. Traditionally focal ischaemia models involved permanent occlusion of a major cerebral artery such as the MCA. However, since vessel occlusion is seldom permanent in human stroke more recent developments have incorporated reperfusion (following ischaemia) into the design of the animal model. This has been achieved by reversible occlusion of cerebral vessels using 1) intraluminal filaments; 2) microclips; 3) the abluminal application of potent and prolonged vasoconstrictors; or 4) the introduction of emboli into the cerebral circulation.(ABSTRACT TRUNCATED AT 250 WORDS)