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Biomedical subjects

C Z Zhu

Publications and source records attributed to C Z Zhu.

15 recordsLinked to original sources
PubMed2001

A-134974: a novel adenosine kinase inhibitor, relieves tactile allodynia via spinal sites of action in peripheral nerve injured rats.

Extracellular levels of adenosine (ADO) can be raised through inhibition of adenosine kinase (AK), a primary metabolic enzyme for ADO. AK inhibitors have shown antinociceptive activity in a variety of animal models of nociception. The present study investigated the antinociceptive actions of a novel and selective AK inhibitor, A-134974 (IC(50)=60 pM), in a rat model of neuropathic pain (ligations of the L5/L6 spinal nerves) and explored the relative contributions of supraspinal, spinal and peripheral sites to the actions of A-134974. Systemic A-134974 dose-dependently reduced tactile allodynia (ED(50)=5 micromol/kg, i.p.) for up to 2 h. Fall latencies in the rotorod test of motor coordination were unaffected by systemic administration of A-134974 (at doses up to 30 micromol/kg, i.p.). Administration of A-134974 intrathecally (i.t.) was more potent (ED(50)=10 nmol) in relieving tactile allodynia than delivering the compound by intracerebroventricular (ED(50)>100 nmol, i.c.v.) or intraplantar (ED(50)>500 nmol) routes suggesting that spinal sites of action are the primary contributors to the anti-allodynic action of A-134974. The anti-allodynic effects of systemic A-134974 (10 micromol/kg, i.p.) were antagonized by the non-selective ADO receptor antagonist, theophylline (30-500 nmol) administered i.t. These data demonstrate that the novel AK inhibitor A-134974 potently reduces tactile allodynia through interactions with spinal sites and adds to the growing evidence that AK inhibitors may be useful as analgesic agents in a broad spectrum of pain states.

Adenosine Kinase↗
PubMed2001

Effects of A-134974, a novel adenosine kinase inhibitor, on carrageenan-induced inflammatory hyperalgesia and locomotor activity in rats: evaluation of the sites of action.

The present study investigated 1) antihyperalgesic actions of a novel and selective adenosine kinase (AK) inhibitor, A-134974 (IC(50) = 60 pM), in the carrageenan model of thermal hyperalgesia; 2) effects of A-134974 on locomotor activity; and 3) relative contributions of supraspinal, spinal, and peripheral sites to the actions of A-134974. Systemic A-134974 (i.p.) dose dependently reduced hyperalgesia (ED(50) = 1 micromol/kg) and at higher doses, reduced locomotor activity (ED(50) = 16 micromol/kg). Administration of A-134974 intrathecally (i.t.) was more potent (ED(50) = 6 nmol) at producing antihyperalgesia than delivering the compound by intracerebralventricular (ED(50) = 100 nmol, i.c.v.) or intraplantar (ED(50) >300 nmol) routes. In contrast, i.c.v. administration of A-134974 was more effective in reducing locomotor activity than i.t. administration (ED(50) values were 1 and >100 nmol, respectively). Increasing the pretreatment time for i.t.-delivered A-134974 caused a greater reduction in locomotor activity (ED(50) = 10 nmol). This was due to diffusion of A-134974 (i.t.) to supraspinal sites. The antihyperalgesic effects of systemic A-134974 were antagonized by the adenosine receptor antagonist theophylline (THEO, 30-500 nmol) administered i.t., but not i.c.v. In the locomotor assay, i.t.-injected THEO did not antagonize hypomobility caused by systemic or i.t. administration of A-134974. However, i.c.v. infusion of THEO did block the hypomotive actions of i.c.v.-, i.t.-, and i.p.-administered A-134974. These data demonstrate that the novel AK inhibitor A-134974 potently reduces thermal hyperalgesia primarily through interactions with spinal sites, whereas its ability to depress locomotor activity is predominantly mediated by supraspinal sites.

Adenosine Kinase↗
PubMed2000

ABT-627, an endothelin ET(A) receptor-selective antagonist, attenuates tactile allodynia in a diabetic rat model of neuropathic pain.

Tactile allodynia, the enhanced perception of pain in response to normally non-painful stimulation, represents a common complication of diabetic neuropathy. The activation of endothelin ET(A) receptors has been implicated in diabetes-induced reductions in peripheral neurovascularization and concomitant endoneurial hypoxia. Endothelin receptor activation has also been shown to alter the peripheral and central processing of nociceptive information. The present study was conducted to evaluate the antinociceptive effects of the novel endothelin ET(A) receptor-selective antagonist, 2R-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N, N-di(n-butyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid (ABT-627), in the streptozotocin-induced diabetic rat model of neuropathic pain. Rats were injected with 75 mg/kg streptozotocin (i. p.), and drug effects were assessed 8-12 weeks following streptozotocin treatment to allow for stabilization of blood glucose levels (>/=240 mg/dl) and tactile allodynia thresholds (</=8.0 g). Systemic (i.p.) administration of ABT-627 (1 and 10 mg/kg) was found to produce a dose-dependent increase in tactile allodynia thresholds. A significant antinociceptive effect (40-50% increase in tactile allodynia thresholds, P<0.05) was observed at the dose of 10 mg/kg, i.p., within 0.5-2-h post-dosing. The antinociceptive effects of ABT-627 (10 mg kg(-1) day(-1), p.o.) were maintained following chronic administration of the antagonist in drinking water for 7 days. In comparison, morphine administered acutely at a dose of 8 mg/kg, i.p., produced a significant 90% increase in streptozotocin-induced tactile allodynia thresholds. The endothelin ET(B) receptor-selective antagonist, 2R-(4-propoxyphenyl)-4S-(1, 3-benzodioxol-5-yl)-1-(N-(2, 6-diethylphenyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxy lic acid (A-192621; 20 mg/kg, i.p.), did not significantly alter tactile allodynia thresholds in streptozotocin-treated rats. Although combined i.p. administration of ABT-627 and A-192621 produced a significant, acute increase in tactile allodynia thresholds, this effect was significantly less than that produced by ABT-627 alone. These results indicate that the selective blockade of endothelin ET(A) receptors results in an attenuation of tactile allodynia in the streptozotocin-treated rat.

Analgesics, Non-Narcotic↗
PubMed2000

ABT-702 (4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin- 3-yl)pyrido[2,3-d]pyrimidine), a novel orally effective adenosine kinase inhibitor with analgesic and anti-inflammatory properties. II. In vivo characterization in the rat.

Adenosine kinase (AK; EC 2.7.1.20) is a key intracellular enzyme regulating intra-and extracellular concentrations of adenosine (ADO), an endogenous neuromodulator, antinociceptive, and anti-inflammatory autocoid. AK inhibition provides a means of potentiating local tissue concentrations of endogenous ADO, and AK inhibitors may have therapeutic potential as analgesic and anti-inflammatory agents. The effects of ABT-702, a novel, potent (IC(50) = 1.7 nM), and selective non-nucleoside AK inhibitor were examined in rat models of nociception and acute inflammation. ABT-702 was orally effective and fully efficacious to suppress nociception in a spectrum of pain models in the rat, including carrageenan-induced thermal hyperalgesia, the formalin test of persistent pain, and models of nerve injury-induced and diabetic neuropathic pain (tactile allodynia after L5/L6 spinal nerve ligation or streptozotocin injection, respectively.) ABT-702 was especially potent at relieving inflammatory thermal hyperalgesia (ED(50) = 5 micromol/kg p.o.). ABT-702 was also effective in the carrageenan-induced paw edema model of acute inflammation (ED(50) = 70 micromol/kg p.o.). The antinociceptive and anti-inflammatory effects of ABT-702 were blocked by selective ADO receptor antagonists, consistent with endogenous ADO accumulation and ADO receptor activation as a mechanism of action. The antinociceptive effects of ABT-702 were not blocked by the opioid antagonist naloxone. In addition, ABT-702 showed less potential to develop tolerance to its antinociceptive effects compared with morphine. ABT-702 had no significant effect on rotorod performance or heart rate (at 30-300 micromol/kg p.o.), mean arterial pressure (at 30-100 micromol/kg p.o.), or exploratory locomotor activity (at </=10 micromol/kg p.o.). Thus, ABT-702 is a novel, non-nucleoside AK inhibitor, with a nonopioid, non-nonsteroidal anti-inflammatory drug mechanism of action, which shows antinociceptive and anti-inflammatory activity in vivo.

Adenosine Kinase↗
PubMed1995

Graded hypotension and MCA occlusion duration: effect in transient focal ischemia.

The first 2 h of middle cerebral artery occlusion (MCAO) are likely critical in determining the final outcome in ischemic stroke. To study this early postischemic period, male Wistar rats (n = 161) were subjected to right MCAO with closely spaced step variations in both duration of MCAO and blood pressure (BP), using the intraluminal suture technique. Quantitative neuropathology was performed at 25 coronal planes of the brain after 1-week survival. Atrophy was measured as the difference between the two hemispheres and was added to cortical and striatal necrosis to obtain total tissue loss. Damage consistently increased monotonically with increasing duration of occlusion only when infarct size was expressed as percentage of the contralateral hemisphere, but not when expressed as mm3, because of variable tissue size. The results showed that already at 1 week, the quantity of tissue loss due to resorption and transsynaptic effects approached the quantity of geographically traceable necrosis in cortex and striatum. Minimum brain damage (5%) occurred after 60 min at a BP of 80 mm Hg, with almost no cortical necrosis. Damage was extremely sensitive to hypotension and MCAO duration. At a BP of 40 mm Hg, 60 min of MCAO produced 25% damage, accelerating every 20 min during the 2-h period studied. At BP 80 mm Hg, 120 min of MCAO produced the same damage as only 80 min of MCAO at BP 60 mm Hg. At 60-, 80-, 100-, and 120-min duration of MCAO, infarct size was significantly reduced with increasing BP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Intraventricular administration of insulin and IGF-1 in transient forebrain ischemia.

A beneficial effect of insulin in reducing cerebral ischemic damage has been recently demonstrated, and a direct central mechanism of insulin action in cerebral ischemia has been proposed. To test the hypothesis that one of the neuroprotective mechanisms of insulin action involves a direct interaction with CNS tissue via a growth factor effect, a continuous intraventricular infusion of two doses of insulin and of insulin-like growth factor 1 (IGF-1) was given to fed Wistar rats subjected to 10 min, 15 s of transient forebrain ischemia. Quantitative neuropathology after 1-week survival showed that low-dose insulin (7 IU/rat/day; n = 10) reduced selective necrosis in the striatum (p = 0.015) and one level of the hippocampus (p = 0.023) as compared with animals infused with phosphate-buffered saline (200 microliters/rat/day; n = 8). IGF-1 (50 micrograms/rat/day; n = 8) significantly ameliorated hippocampal damage in four of the six hippocampal levels (p < 0.05). High-dose insulin infusion (23 IU/rat/day; n = 8) produced a robust reduction in cortical (p = 0.0108), striatal (p = 0.003), and hippocampal (p < 0.05) necrosis at all coronal levels. However, this high-dose insulin reduced the blood sugar significantly (p < 0.01), from 11.8 to 7.8 mM, probably by virtue of centrally administered insulin reaching the periphery. We conclude that insulin and IGF-1 offer a moderate, centrally mediated, neuroprotective effect, likely mediated at least in part via a growth factor mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Centrally administered insulin and IGF-1 in transient forebrain ischaemia in fasted rats.

Based on evidence for a direct central mechanism of insulin action in mitigating damage due to cerebral ischaemia, we have recently shown that centrally administered insulin, and to a lesser extent, insulin-like growth factor-1 (IGF-1), reduce ischaemic damage in fed rats. Because a portion of the neuroprotective effect of insulin may be due to peripheral hypoglycaemia, we undertook the present series of experiments to determine whether insulin or IGF-1 are neuroprotective in fasted rats, which already have low blood glucose values. Continuous minipump delivery of insulin (1 IU rat-1 day-1 n = 13), or IGF-1 (50 micrograms rat-1 day-1 n = 10) was compared to control rats treated with phosphate buffered saline (PBS 25 microliters rat-1 day-1 n = 10). Quantitative neuropathology was done one week after 10 min and 15 sec of transient forebrain ischaemia induced by bilateral carotid artery clamping at a mean arterial BP (MABP) of 50 mmHg. In all areas examined i.e. neocortex, striatum, and hippocampus, the three groups showed similar degrees of necrosis (p > 0.05), although there were insignificant trends for a beneficial effect of insulin in reducing selective neuronal necrosis in hippocampus. The results, in combination with previous studies, indicate that insulin is more effective in attenuating brain damage in fed rats.

Animals↗
PubMed1992

Silent stroke and carotid stenosis.

BACKGROUND AND PURPOSE: Silent cerebral infarction is often found on computed tomographic scan in patients with asymptomatic carotid stenosis, but its relation to the arterial stenosis is uncertain. METHODS: We compared computed tomographic scans and carotid Doppler in 115 patients with asymptomatic carotid stenosis, 203 with carotid transient ischemic attacks and carotid stenosis, and 63 with transient ischemic attacks but without carotid stenosis. There was no group with normal carotid arteries for comparison. RESULTS: Lesions seen on CT scan were most common in the transient ischemic attack with carotid stenosis group (47%) compared with the other groups (30%, 19%) (p less than 0.001). Cerebral infarcts ipsilateral to the carotid stenosis were found in 10% of patients with mild (35-50%) stenosis, 17% in moderate (50-75%) stenosis, and 30% with severe (greater than 75%) carotid stenosis (p less than 0.001). In patients with asymptomatic carotid stenosis, 68% of infarcts were ipsilateral to the stenosis; in those with transient ischemic attacks and carotid stenosis, 86% of infarcts were ipsilateral to the stenosis. CONCLUSIONS: The more severe the carotid stenosis, the higher the incidence of cerebral infarction ipsilateral to the stenosis. This finding applied to central infarcts as well as to peripheral infarcts in both symptomatic and asymptomatic patients. Silent cerebral infarction may be an indication for carotid endarterectomy in asymptomatic patients.

Aged↗
PubMed1991

Vascular risks of asymptomatic carotid stenosis.

BACKGROUND AND PURPOSE: We sought to determine the risks of stroke, myocardial ischemia, and vascular death in patients with asymptomatic carotid stenosis. METHODS: Six hundred ninety-six patients with asymptomatic carotid stenosis referred to the Doppler laboratory were followed prospectively for a mean time of 41 months. These patients were studied both clinically and by carotid Doppler ultrasound, including evaluation of the effect of stroke risk factors. RESULTS: Transient ischemic attacks occurred in 75 patients and stroke in 29, while 132 had ischemic cardiac events. Five patients died from stroke and 59 from cardiac causes. Annual stroke rate was 1.3% in patients with carotid stenosis less than or equal to 75% and 3.3% in those with stenosis greater than 75%. Ipsilateral stroke rate was 2.5% in patients with greater than 75% carotid stenosis. Annual cardiac event rate was 8.3% and death rate 6.5% in patients with severe carotid stenosis. CONCLUSIONS: With carotid stenosis less than or equal to 75%, the stroke rate is negligible (1.3% annually) whereas the combined risk of cardiac ischemia and vascular death is as high as 9.9%. With stenosis greater than 75%, combined transient ischemic attack and stroke rate is 10.5% per year, with 75% of events ipsilateral to the stenosed artery.

Aged↗
PubMed1991

A therapeutic window for carotid endarterectomy in patients with asymptomatic carotid stenosis.

The natural history of asymptomatic carotid stenosis was prospectively and systematically studied in 500 patients by clinical observation and carotid Doppler ultrasonography. In the 40% of carotid arteries (398) with an initial stenosis of over 35%, there were apparently two separate populations, with a cutoff point of 85% stenosis. There were 79 ischemic cerebral events (54 transient ischemic attacks and 25 strokes) among the 500 patients during 60 months of follow-up, predominantly in the severe-stenosis (more than 75%) group, with few events occurring in the near-or total-occlusion (95% to 100% stenosis) group; the highest incidence was in patients whose arteries had 75% to 90% stenosis. These observations indicate a critical degree of carotid stenosis at which stroke risk becomes maximal, declining as the artery becomes occluded. These findings suggest that there may be a "window" for carotid endarterectomy in patients with asymptomatic carotid stenosis, when the stroke risk may be high enough (5.5%/year) to warrant surgery.

Auscultation↗
PubMed1990

Stroke risk and critical carotid stenosis.

The risk of stroke from carotid stenosis is proportionate to the degree of stenosis, but whether this is a direct and linear relationship is unknown. Using the degree of carotid stenosis in 500 patients with asymptomatic carotid bruits as a continuous variable, we plotted the frequency distribution and related this to the risk of ischaemic cerebral events and the progression of the arterial lesion. There was a bi-modal distribution, with the junction of the two populations at 85% stenosis. The frequency of ischaemic cerebral events was maximal at 75-90% stenosis. Our data suggest that there is a critical degree of carotid stenosis at which stroke risk becomes maximal. This may represent a window of therapeutic opportunity.

Carotid Artery Diseases↗
PubMed1990

Role of carotid stenosis in ischemic stroke.

Using Doppler ultrasonography, we evaluated the frequency and severity of carotid artery stenosis in 261 patients with carotid ischemic strokes, 813 patients with carotid transient ischemic attacks, 500 patients with asymptomatic neck bruits, and 500 controls. Most patients with strokes and transient ischemic attacks had no associated carotid artery disease (55% and 64%, respectively), and such patients without neck bruits were even more likely to be without carotid artery disease (69% and 77%, respectively). Carotid stenosis was more frequent and more likely to be severe in symptomatic than in asymptomatic patients (p less than 0.0002), even after adjusting for age and sex. Carotid stenosis is present in only a minority of patients with strokes and transient ischemic attacks, especially if neck bruits are absent, and the cause of the ischemic cerebral events in most of these patients remains unexplained.

Age Factors↗