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J Krupinski

Publications and source records attributed to J Krupinski.

At least 19 recordsLinked to original sources
PubMed2006

Pathophysiology of acute ischaemic stroke: an analysis of common signalling mechanisms and identification of new molecular targets.

Stroke continues to be a major cause of death and disability. The currently available therapies have proven to be highly unsatisfactory (except thrombolysis) and attempts are being made to identify and characterize signalling proteins which could be exploited to design novel therapeutic modalities. The pathophysiology of stroke is a complex process. Delaying interventions from the first hours to days or even weeks following blood vessel occlusion may lead to worsening or impairment of recovery in later stages. The objective of this review is to critically evaluate the major mechanisms underlying stroke pathophysiology, especially the role of cell signalling in excitotoxicity, inflammation, apoptosis, neuroprotection and angiogenesis, and highlight potential novel targets for drug discovery.

Animals↗
PubMed2005

Citicoline inhibits MAP kinase signalling pathways after focal cerebral ischaemia.

The link between membrane phospholipids and different intracellular signal transduction pathways affected by cerebral ischaemia is unclear. CDP-choline, a major neuronal membrane lipid precursor and its intracellular target proteins and transcription factors were studied to further understand its role in ischaemic stroke. Cerebral ischaemia was produced by distal, permanent occlusion of the middle cerebral artery (MCAO) in the rat. Animals receiving 500 mg/kg of CDP-choline in 0.5 ml of 0.9% saline, intraperitoneally, 24 h and 1 h before MCAO and 23 h after MCAO demonstrated a notable reduction in the phosphorylation of MAP-kinase family members, ERK1/2 and MEK1/2, as well as Elk-1 transcription factor, compared with control animals treated with 0.5 ml of 0.9% saline. Immunohistochemistry showed a particular reduction in immunoreactivity in glia. The effects of CDP-choline on intracellular mechanisms of signal transduction, suggests that this molecule may play a key role in recovery after ischaemic stroke.

Animals↗
PubMed2003

Time-course phosphorylation of the mitogen activated protein (MAP) kinase group of signalling proteins and related molecules following middle cerebral artery occlusion (MCAO) in rats.

Recovery from the debilitating effects of ischaemic stroke is variable and unpredictable. To maximize patient recovery, a greater understanding of the molecular mechanisms involved in regulating both apoptosis and the repair processes affecting neuronal protection, particularly in the penumbra region, is desirable. We have previously shown, in human subjects, the increased expression of several growth factors soon after stroke, together with appearance of tyrosine phosphorylated proteins, in particular mitogen activated protein (MAP) kinase (ERK1/2). In this paper, we demonstrate a relatively short-lasting (< 12 h), but substantial increase in expression of phosphorylated proteins, in particular, p-JNK (phosphorylated c-Jun N-terminal kinase) and p-ERK1/2 in both the grey matter penumbra and infarcted tissue of rats, following permanent middle cerebral artery occlusion. p-ERK1/2 was associated with neurones and endothelial cells in the vicinity of the infarct while p-JNK was mainly expressed in neurones. Expression of both p-MEK3/6 and p-p38 MAP kinase was also increased in neurones and astroglia, within 1 h of infarction, p-p38 remaining elevated and associated with neurones and in particular with astroglia in the penumbra region for > 4 days. Evidence suggests that short-term activation of these proteins may be detrimental to neuronal survival, while their transient nature makes them unlikely to support angiogenesis, revascularization and reperfusion over a period of days and weeks. On the other hand, short-medium-term up-regulation of neuronal p-JNK, p-c-Jun, p-Stat-1 and p-p38 might be a factor in the regulation of apoptosis. Therapeutic manipulation of phosphorylation/activation of these and other important signalling intermediates might form the basis of an appropriate treatment to maximize revascularization and neuronal protection after ischaemic stroke.

Animals↗
PubMed2002

CDP-choline reduces pro-caspase and cleaved caspase-3 expression, nuclear DNA fragmentation, and specific PARP-cleaved products of caspase activation following middle cerebral artery occlusion in the rat.

Citicoline has been demonstrated to be beneficial in several models of cerebral ischaemia. We tested the hypothesis that citicoline may provide apoptotic pathways following focal cerebral ischaemia. Focal cerebral ischaemia was produced by distal, permanent middle cerebral artery occlusion (MCAO) in Sprague-Dawley rats. The animals were randomised into four groups: (B+A) Citicoline 500 mg/kg IP 24 and 1 h before MCAO, and 23 h after MCAO; (A) citicoline 500 mg/kg IP, within 30 min after MCAO, and 23 h after MCAO; (C) vehicle IP; and (D) sham-operated. The animals were sacrificed at 12 h (n=8 per group) and 24 h (n=8 per group) after MCAO. Immunohistochemistry was performed on free-floating tissue sections with goat polyclonal antibodies to procaspase-1, -2, -3, -6 and -8, and in paraffin-embedded sections processed for cleaved caspase-3 (17 kDa) immunohistochemistry. Finally, some sections were stained with the method of in situ end-labelling of nuclear DNA fragmentation. For gel electrophoresis and Western blotting, antibodies to poly (ADP-ribose) polymerase (PARP) products of 89 kDa were used to reveal specific cleavage substrates of caspases. MCAO induced the expression of all procaspases and the expression of PARP products of 89 kDa, as well as cells with nuclear DNA fragmentation, at 12 and 24 h, in the infarcted core and penumbra. Citicoline reduced the expression of all procaspases at 12 and 24 h after MCAO, as well as the expression of cleaved caspase-3 in cells in the penumbra area. This was accompanied by a reduction in the number of cells bearing nuclear DNA fragments. The expression of caspase-cleaved products of PARP (PARP 89 kDa) was reduced in citicoline-treated ischaemic rats. These results show that citicoline inhibits the expression of proteins involved in apoptosis following MCAO.

Animals↗
PubMed2001

The discovery of novel, potent and selective PDE5 inhibitors.

The design and synthesis of a novel scaffold for potent and selective PDE5 inhibitors are described. Compound 3a was more potent (PDE5 IC50=0.31 nM) and selective (>10,000-fold vs PDE1 and 160-fold selective vs PDE6) PDE5 inhibitor than sildenafil.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2001

Brain-derived neurotrophic factor reduces cortical cell death by ischemia after middle cerebral artery occlusion in the rat.

Stroke is the major cause of adult brain dysfunction. In an experimental approach to evaluate the possible beneficial effects of administration of neurotrophic factors in stroke, we have used a model of distal middle cerebral artery (MCA) occlusion in adult rats. In this model, we found: (1) a permanent reduction of brain-derived neurotrophic factor (BDNF) and its full-length receptor, TrkB, in the infarcted core; (2) a transient increase in BDNF immunoreactivity in the internal region of the border of the infarct (penumbra area) at 12 h after MCA occlusion; (3) increased truncated TrkB immunoreactivity in astrocytes surrounding the area of the infarction; and (4) increased full-length TrkB immunoreactivity in scattered neurons, distant from the infarct, in ipsilateral and contralateral cortices at 24 and 48 h after MCA occlusion. We next studied the regulation of TrkB expression by BDNF, after ischemia, and its neuroprotective effects in vivo. In control non-ischemic rats, grafting of mock- or BDNF-transfected fibroblasts (F3A-MT or F3N-BDNF cell lines, respectively) in the medial part of the somatosensory cortex increased truncated TrkB immunoreactivity in neighboring astrocytes. Grafting alone also increased full-length TrkB in the vicinity of the mock graft (at 24 and 48 h) and the BDNF-grafted graft (at 4 days). Interestingly, ischemic animals grafted with the mock-transfected cell line did not show any further regulation of TrkB receptors. However, ischemic animals grafted with the BDNF cell line showed an up-regulation of full-length TrkB expression in neurons located in the internal border of the infarct. Analysis of nuclear DNA fragmentation in situ, combined with microtubule-associated protein 2 immunohistochemistry, revealed that most cells dying in the borders of the infarct (penumbra area) at 48 h following MCA occlusion were neurons. No differences in the infarct size were found between MCA occluded, mock-transfected MCA-occluded, and BDNF-transfected MCA-occluded rats. Moreover, cell death was similar in nongrafted and mock-grafted rats subjected to MCA occlusion. However, the number of cells with nuclear DNA breaks was significantly reduced in the penumbra area close to the BDNF graft in ischemic rats. Thus, our results show that BDNF specifically up-regulates its full-length TrkB receptor in cortical neurons of the penumbra area and prevents their death in an in vivo model of focal ischemia.

Animals↗
PubMed2001

The identification and treatment of depression by general practitioners.

OBJECTIVE: To assess the level of recognition and knowledge about treatment of depression by General Practitioners (GPs). METHOD: Analysis of questionnaires completed by participants commencing a series of workshops aimed at improving their knowledge of the diagnosis and treatment of depression. Of the 3289 GPs involved in the program 2500 (76% respondent rate) completed the questionnaires in a group situation. There was no difference between respondents and nonrespondents in terms of age, gender and year of graduation. RESULTS: The majority of GPs believe they have a satisfactory competence in the recognition and treatment of depression, although a sizeable minority based their diagnosis predominantly on somatic symptoms. The GPs felt confident about their knowledge and skills in counselling and the use of antidepressant medication, but not in dealing with children and suicidal or pregnant patients. The most common symptoms used to identify 'depression' were sleep disorders and only 54% listed depressed mood as a symptom on which the diagnosis is based. Only 28% reported sufficient symptoms to meet criteria for DSM-IV major depressive disorder, which supports views that these criteria are inappropriate for general practice. Fifty-seven percent of doctors used medicine together with nonpharmacological treatment in the majority of patients, and medications doses were almost all within the range recommended in the product information. CONCLUSIONS: There is a need to improve GPs knowledge in diagnosing depression, in child psychiatry and in dealing with pregnant and suicidal patients.

Adult↗
PubMed2000

Optimization of substituted N-3-benzylimidazoquinazolinone sulfonamides as potent and selective PDE5 inhibitors.

A previous report from these laboratories identified the N-3-benzylimidazoquinazolinone nucleus as a more selective PDE5 inhibitor template compared to the pyrazolopyrimidine of sildenafil. This paper describes in detail the structure-activity relationships of a set of sulfonamide analogues, several of which are both more potent and more selective PDE5 inhibitors in vitro than sildenafil. The synthesis, in vitro enzyme activity and selectivity, and in vitro functional and preclinical pharmacokinetic assessment of molecules in this series are described.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2000

Activation of MAP kinase (ERK-1/ERK-2), tyrosine kinase and VEGF in the human brain following acute ischaemic stroke.

We examined expression of vascular endothelial growth factor (VEGF), phosphorylation of mitogen activated protein kinase (MAP) kinase (ERK1 and ERK2) and tyrosine phosphorylation in 19 patients (aged 58-90 years; mean 75) who died 1-44 days after acute ischaemic stroke. In the grey matter penumbra, 13 of 19 patients showed an increase in MAP kinase tyrosine phosphorylation (ERK1; 2.0- to 8-fold, ERK2; 2.2- to 11-fold) compared with normal contralateral tissue. In almost all cases, ERK-2 phosphorylation was higher than ERK1. Of these 13 patients, 11 also showed a general increase in tyrosine kinase phosphorylation, and eight expressed increased levels of VEGF protein (2.5- to 5-fold). In tissue examined directly from the infarct core, activation of the above proteins was not observed in the, majority of patients. In the white matter, seven of 19 patients (penumbra), and nine of 19 patients (stroke) had an increase in MAP kinase tyrosine phosphorylation (ERK1; 2.0- to 4.6-fold and ERK-2; 2.3- to 5.4-fold respectively) compared with normal contralateral tissue. There was no relationship between activation of MAP kinase and expression of VEGF. Examination of phosphorylated MAP kinase by immunohistochemistry revealed an increase in immunoreactivity in neurones, astroglial cells, reactive microglia and endothelial cells in areas surrounding infarcts, especially in areas with the highest density of microvessels. In conclusion, chronic activation of tyrosine phosphorylated events, in particular redistribution and phosphorylation of MAP kinase (ERK1/ERK2) occurs consistently in the grey matter penumbra of brain tissue following ischaemic stroke, and may be associated with increase in expression of VEGF. These signal transduction events could be important determinants of the extent of neuronal survival and/or angiogenic activity in the recovering brain tissue.

Acute Disease↗
PubMed2000

N-3-substituted imidazoquinazolinones: potent and selective PDE5 inhibitors as potential agents for treatment of erectile dysfunction.

Phosphodiesterase type 5 (PDE5) inhibitors with improved PDE isozyme selectivity relative to sildenafil may result in agents for the treatment of male erectile dysfunction (MED) with a lower incidence of PDE-associated adverse effects. This paper describes the discovery of 14, a PDE5 inhibitor with improved potency and selectivity in vitro compared to sildenafil. This compound shows activity in a functional assay of erectile function comparable to that of sildenafil.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2000

Expression of caspases and their substrates in the rat model of focal cerebral ischemia.

Experimental evidence suggests that the massive release of glutamate during experimental brain ischemia both directly and indirectly regulates downstream mechanisms of cell suicide. Cerebral ischemia was produced by distal, permanent occlusion of the middle cerebral artery (MCAO) in the rat. Sets of three animals and one sham-operated for each time-point were kept alive for 0-30 min, 1, 4, 12, 24, and 48 h, and 4 days. Additional animals were treated by local administration of a 10 microM (in 10 microl) cocktail of caspase inhibitors (YVAD-cmk, DEVD-fmk, IETD). Immunohistochemistry was performed on free-floating tissue sections with goat polyclonal antibodies to procaspase-1, -2, -3, -6, and -8. Some sections were processed for double-labeling procaspase immunohistochemistry and in situ end-labeling of nuclear DNA fragmentation (TUNEL method). Both immunohistochemistry and double-labeling procaspase immunohistochemistry and TUNEL method were carried out on formalin-fixed sections. For gel electrophoresis and Western blotting, we used antibodies to poly (ADP-ribose) polymerase (PARP), lamin B, and PKC-delta, as specific cleavage substrates of caspases. There was increased immunoreactivity ipsilaterally in the areas corresponding to the infarct and surrounding penumbra with the peak of immunoreactivity between 12 and 24 h for most of the procaspases. Procaspases were present early in the infarcted tissue neurones and their dendrites and axons. Additional procaspase expression occurred in astrocytes and microglial cells at different times following ischemia. Cells with positive in situ end-labeling of nuclear DNA fragmentation appeared in high number predominantly in the infarcted areas and at the edge of the infarction and colocalized with enhanced procaspase expression. These findings suggest increased procaspase expression in dying cells at the edge of the infarction. A major product of PARP degradation of about 89 kDa was found in the samples taken from the infarcted and penumbra areas. There was no difference in the intensity of the bands corresponding to lamin B or PKC-delta. Injection of procaspase inhibitors reduced the levels of major PARP products of 89 kDa and decreased the number of TUNEL-positive cells at 12 h post-MCAO. In conclusion, these results give support to further research on the use of caspase inhibitors as add-on therapeutic agents for the treatment of ischemia.

Animals↗
PubMed2000

Differential c-Fos and caspase expression following kainic acid excitotoxicity.

Caspases play crucial roles in the inflammatory response and in the cell pathway leading to apoptosis. Caspase 1 (ICE), 2 (Nedd2), 3 (CPP32), 6 (Mch2) and 8 (Mch5, FLICE) expression was examined using immunohistochemistry in the brains of rats and gerbils following systemic administration of kainic acid (KA). The distribution of caspase expression was compared with the distribution of c-Fos expression, a transcription factor that is produced in response to the excitotoxic insult. Strong caspase 2 immunoreactivity was found in microglia up to 6 h following KA administration. Focal strong expression of caspases 1, 2, 3, 6 and 8 was observed in astrocytes and neurons, from 12 to 48 h after KA injection, in areas in which a number of neurons were committed to die. This distribution was in contrast with the generalised distribution of c-Fos expression following KA administration. Only a minority of neurons in the entorhinal cortex, amygdala and hilus, but a majority of neurons in selected thalamic nuclei, exhibited strong caspase expression in KA-treated rats. Similar findings, although minimised, were observed in KA-treated gerbils. Double-labelling caspase immunohistochemistry and in situ end-labelling of nuclear DNA fragmentation disclosed co-localisation of strong caspase expression and nuclear DNA breaks in a small percentage of neurons but no co-localisation in astrocytes. Western blots of entorhinal cortex and neocortex homogenates showed cleavage of certain caspase substrates in KA-treated rats. The intensity of the bands corresponding to lamin B and protein kinase C-delta was decreased in the entorhinal cortex following KA administration. Several bands appeared in the entorhinal cortex and neocortex paragraph signin Western blots processed for the demonstration of poly(ADP-ribose) polymerase (PARP), thus indicating that other proteases, in addition to caspases, cleaved PARP following KA administration. Taken together, these findings indicate that KA excitotoxicity triggers caspase expression which, although predominant in regions subjected to irreversible cell damage, has only a weak association with the presence of nuclear DNA breaks and neuron cell death. Although these results suggest caspase activation, further studies have to be performed to elucidate whether caspase activation plays a crucial role in KA excitotoxicity.

Animals↗
PubMed2000

Factors influencing the frequency of fluorescence transients as markers of peri-infarct depolarizations in focal cerebral ischemia.

BACKGROUND AND PURPOSE: Peri-infarct depolarizations (PIDs) that occur in ischemic boundary zones of the cerebral cortex of experimental animals have been shown to promote rather than simply to indicate the evolution of the lesion and are especially prominent in the rat. To study the influence of one factor, species, on PID incidence, we compared the frequency of PIDs in a primate species, the squirrel monkey, with that in the cat after middle cerebral artery occlusion. Plasma glucose was reviewed as a possible cause of interexperiment variability in the cat experiments. METHODS: In open-skull experiments under chloralose anesthesia, changes in cortical fluorescence believed to indicate NADH/NAD(+) redox state, as markers of PIDs, were recorded by serial imaging of the cortical surface in vivo for 4 hours after middle cerebral artery occlusion. RESULTS: Fluorescence transients occurred in squirrel monkeys at a frequency (mean+/-SD) of 0.7+/-0.8 hours(-1) (n=5), which was not significantly less than in that observed in cats (1.3+/-1.6 hours(-1), n=8). Data from the cat experiments indicated a relationship between number of transients (dependent) and plasma glucose, with a striking increase in PID frequency in association with values of mean postocclusion plasma glucose <4.1 mmol/L (Mann-Whitney U=15.0, P=0.034); this observation agrees well with other published findings. CONCLUSIONS: Transient changes in fluorescence strongly suggestive of peri-infarct depolarizations, either transient or terminal, occur and propagate in the ischemic cerebral cortex of a nonhuman primate. The results also suggest that the relationship of frequency of peri-infarct depolarizations with plasma glucose requires further examination, to confirm the finding and to determine a safe lower limit for a target range for control of plasma glucose if insulin is used in the management of patients with cerebral ischemia.

Action Potentials↗
PubMed2000

Serial measurement of vascular endothelial growth factor and transforming growth factor-beta1 in serum of patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: Both vascular endothelial growth factor (VEGF) and transforming growth factor-beta1 (TGF-beta1) are expressed in higher than normal concentrations in the penumbra of patients after ischemic stroke. Because both cytokines are central to the processes of angiogenesis, tissue inflammation, and fibrosis, we performed serial measurements of these cytokines in patients with cerebral infarction and determined their relationship to stroke etiology and volume. METHODS: We serially (at days 0, 1, 3, 7, and 14) measured the serum levels of VEGF and active TGF-beta1 in 29 patients with acute ischemic stroke. Age-matched healthy subjects (n=26) were used as controls. RESULTS: Expression of VEGF was significantly increased in the majority of patients after acute stroke at each of the time points compared with normal controls. Highest expression occurred at day 7 (588+/-121 pg/mL; P=0.005), and it remained significantly elevated at 14 days after stroke. Expression of VEGF correlated with infarct volume, clinical disability (Scandinavian Stroke Scale), and peripheral leukocytosis and was significantly higher in patients with atherothrombotic large-vessel disease and ischemic heart disease (P<0.05 in all cases). In contrast, expression of active TGF-beta1 was not significantly different from control patients at any of the measured time points. When the mean concentration of TGF-beta1 from each patient (pooled time points) was compared with the control mean, a significant increase was found in only 2 patients, whereas levels decreased in 12 patients (P<0.05). There was no correlation between circulating active TGF-beta1 and VEGF expression, leukocytosis, stroke subtype, or patient disability as assessed by Scandinavian Stroke Scale score. CONCLUSIONS: VEGF but not TGF-beta1 showed a dramatic increase in serum of stroke patients. Correlation between stroke severity and VEGF concentration suggests it could be involved in the subsequent repair processes resulting in partial recovery after stroke. Correlation between VEGF expression and peripheral leukocytosis suggests that these changes may also reflect the immunologic status of the patient. VEGF may play an important role in the pathophysiology of acute ischemic stroke and could be of value in future treatment strategies.

Acute Disease↗
PubMed1999

Acoustic analysis of dysarthria profile in ALS patients.

Dysarthria is a leading disability in ALS patients with motor neurone degeneration in the bulbar region. Although different approaches have been tried in the past, currently, no test is available to detect and follow the progression of dysarthria. We studied 53 patients with definite (n=27) or probable (n=26) ALS (the bulbar onset group n=15, the limb onset group n=38, mean age 53. 66/29-76 years/) according to El Escorial criteria. Each patient was seen by a neurologist every 10-12 weeks and clinical performance was assessed using the Norris scale. To evaluate dysarthria we developed a computer-based acoustic method. All patients had computer-analysed speech sound tests done three times. The most significantly affected vowels were selected for further studies. A method based on the Euclidian principle was used and the results were compared with 30 age, sex-matched, healthy control subjects. Our results demonstrated the existence of a specific dysarthria profile in ALS patients with most significantly affected vowels: 'B', 'O', 'I', 'W', 'T' in the bulbar group, and: 'B', 'I', 'T', 'W', 'O' in the limb group. This study suggests that it is possible to detect and monitor the progression of the disease based on the acoustic analysis of only several sounds. Abnormalities detected in the dysarthria profile may appear prior to any clinical symptoms of the disease.

Adult↗
PubMed1999

Soluble intercelluar adhesion molecule-1, E-selectin, vascular cell adhesion molecule-1 and von Willebrand factor in stroke.

We investigated the role of endothelial cell and leukocyte adhesion in the pathophysiology of acute stroke. The immunocytochemical expression of adhesion molecules in brain tissue from six patients who died following acute ischaemic stroke showed weak endothelial expression of intercellular adhesion molecule-1 (ICAM-1), but intense expression of vascular cell adhesion molecule-1 (VCAM-1) by astrocytes and endothelial cells from the infarcted, but not the non-infarcted areas. We also measured soluble adhesion molecules E-selectin, ICAM-1, VCAM-1 and von Willebrand factor (all by enzyme-linked immunosorbent assay) in 21 patients after an acute ischaemic stroke (ictus < 12 h), and again 3 months later. Blood levels in the stroke patients were compared with 82 healthy controls and 22 subjects with carotid atherosclerosis. Compared with healthy controls, both patient groups had raised levels of von Willebrand factor (P < 0.02) but the level of soluble VCAM-1 was raised only in patients with acute stroke (P < 0.02). Levels of von Willebrand factor and soluble VCAM-1 in the stroke patients were still high at 3 months follow-up. We suggest that there might be changes in adhesion molecule expression and release in the acute and chronic stages of ischaemic stroke, where blood levels are related to immunocytochemical findings on infarcted brain. These changes may perhaps be part of the complex pathophysiological responses to infarction and repair of brain tissue following stroke.

Aged↗
PubMed1999

Vascular endothelial growth factor and its receptor, KDR, in human brain tissue after ischemic stroke.

Ischemic stroke results from a reduction in cerebral blood flow to a focal region of the brain after the occlusion of an artery, causing damage to nervous tissue. There is a region of cerebral ischemic tissue (penumbra) surrounding an acute cerebral infarct that is dysfunctional but potentially viable. Restoration of perfusion in the penumbra may ameliorate the tissue damage. The identity and the role of growth factors that control the extent of tissue damage and its repair are poorly understood. Angiogenesis has been demonstrated to occur in brain tissues of patients surviving an acute ischemic stroke. In this paper we have investigated the status of a potent angiogenesis factor, vascular endothelial growth factor (VEGF), in patients after acute ischemic brain stroke. Western blotting and immunohistochemistry were used to determine protein expression, and in situ hybridization was used to quantify and localize mRNA synthesis. The expression of VEGF protein was increased in the penumbra compared with infarcted brain and contralateral hemisphere. Neurones, endothelial cells, and astrocytes in the penumbra in all patients studied had significant up-regulation of both VEGF165 and VEGF189 mRNA (p < 0.01, Wilcoxon Matched-Pairs Signed-Ranks Test) compared with infarcted tissue and the normal looking contralateral hemisphere that was used as a control. Immunohistochemistry demonstrated that kinase insert domain receptor was present in blood vessels within the infarct/penumbra and absent from the normal contralateral hemisphere. VEGF, which is important in angiogenesis, may also influence long term neuronal survival, and possibly its modulation may prove to be of therapeutic value for patients with ischemic stroke.

Aged↗