Effect Of Propentofylline Research Articles

Effect of propentofylline on activation of astrocytes in spinal cord in a rat model of diabetic neuropathic pain

Objective To investigate the effect of propentofylline on activation of astrecytes in the spinal cord in a rat model of diabetic neuropathic pain(DNP).Methods Pathogen-free SD rats of both sexes aged 2 months weighing 180-200 g were used in this study.Diabetes was induced by intraperitoneal(IP)1% streptozocin(STZ)60 mg/kg.Blood glucose level was measured before(T1)and at 2,7,14,21,28,35 days after IP STZ injection(T2-7).Diabetes Was confirmed by blood glucose level>16.7 mmol/L.Paw withdrawal threshold to von Frey filament stimulation(PWT)Was measured at T1,T3-7.Induction of neuropathic pain WaS considered successful in ccessful in animals with PWT reduced by more than 50%of the baseline.Twenty animals in which DNP was successfully induced were randomly divided into 2 groups(n=10 each):groupⅠdiabetes meatus(DM)and groupⅡ pmpentofylline(PP).Another 10 age-matched normal rats served as control group(Nc),Grorp PP received IP propentofylline 10 ms/kg once B day for 7 consecutive days starting from T6.The animals were killed at T2 and the lumbar segment of the spinal cord Was removed for determination of glial fibrillary acidic protein(GFAP)in the astmcytes in the spinal cord by immuno-histochemical assay.Results PWT Was aignitlcantly lower at T4-7 in group DM and PP than in control group(NC)and Was significantly higher at T7 in group PP than in group DM.Immuno-himochemical assay showed that GFAP-positive astrocytes in the dorsal hom of the spinal cord was significantly increased in diabetic rats and pmpentofyUine significantly attenuated the increase.Conclusion Inhibition of astwcytes in the spinal cord is involved.m attenuation of diabetic neuropathic pmn by propentofylline. Key words: lndoles; Diabetic neuropathy; Neuralgia; Spinal cord; Astwcytes

Propentofylline rapidly normalizes mitochondrial respiration in a gerbil low flow unilateral forebrain ischemia

The effect of propentofylline on mitochondrial respiratory activity was assessed in gerbils after 30 min of unilateral forebrain ischemia and 5 min of incomplete reperfusion. Cerebral blood flow (CBF) measured by hydrogen clearance was reduced to 12.6±2.1 ml/100 g per min in the ischemic hemisphere. Propentofylline at 10 mg/kg applied intraperitoneally raised CBF to 26.7±3.4 ml/100 g per min ( P<0.05) in ischemic areas, however, CBF remained substantially reduced in comparison to the flow in the non-ischemic hemisphere (52.9±4.1 ml/100 g per min). Mitochondrial ADP-stimulated as well as uncoupled respiration was significantly reduced by approximately 60% after 30 min of ischemia. Since ADP-unstimulated respiration was not reduced, the respiratory control ratio declined markedly. Five minutes after application of propentofylline all indices of the mitochondrial respiratory capacity were normalized despite persisting reduction in CBF.

Effect of propentofylline (HWA 285) on focal ischemia in rats:: Effect of treatment and posttreatment duration on infarct size

Background and purpose: in this study we tested the potentially neuroprotective properties of propentofylline in a model of focal ischemia with long-term, repeated treatment. Methods: 37 male Wistar rats (280–300 g) underwent permanent occlusion of the middle cerebral artery (MCA). Infusion was started 30 min after occlusion of the MCA over a period of 2 h with a dosage of 0.01 mg/kg body weight. Immediately after the termination of infusion repetitive intraperitoneal injections were started. Animals were assigned to four groups: continuous treatment for a period of 12 h with 24-h survival (group A, n=9) or 48-h survival (group B, n=10), continuous treatment for a period of 48 h with 48-h survival (group C, n=9) and placebo (group D, n=9). Infarct size was calculated from brain slices stained with 2,3,5-triphenyltetrazolium chloride. Results: the infarct size was significantly reduced in group C (treatment for 48 h) (163.9±30.5 mm 3) compared to the placebo group (297.4±17.7 mm 3). No effect on infarct size was observed in group A (196.8±37.3 mm 3) and group B (239.6±42.9 mm 3) compared to placebo. Conclusion: continuous i.p. injections of propentofylline over a period of 48 h significantly reduces infarct size in an animal model of focal cerebral ischemia. With shorter periods of continuous administration of the drug and delayed postmortem analysis, reductions in the infarct size did not reach a level of significance. These data show the importance of continuous long-term administration after ischemic stroke in clinical trials to achieve the beneficial effects of neuroprotection by propentofylline.

Clinical Trials of Propentofylline in Vascular Dementia

Summary: The neuroprotective glial cell modulator propentofylline has been used in clinical trials involving more than 800 patients with vascular dementia (VaD). These data derive from two sources: a pooled group of VaD patients from four early phase III European trials, and a multinational European/Canadian phase III study (MN 305) that features a combined randomized withdrawal/delayed onset of progression design to evaluate the effect of propentofylline on disease progression. In the pooled studies, DSM-III-R criteria, Hachinski Ischemia Scores, computed tomography (CT), and magnetic resonance imaging (MRI) were used to select subjects with mild-to-moderate disease; in MN 305, National Institute of Neurological Disorders and Stroke/Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) criteria and neurologic examinations (including CT and MRI scans) were used to select patients with possible or probable VaD. The use of a central rater to assess cerebrovascular disease in neuroradiologic examinations for study MN 305 was considered to be a key feature for reducing the heterogeneity of the VaD patient population. In addition, the inclusion of patients with possible VaD in this trial greatly increased the number of eligible patients; subgroup analyses revealed no substantial differences between patients with probable versus possible VaD, justifying their inclusion in the study. VaD patients exhibited a more pronounced placebo response in global assessments compared with the Alzheimer disease population in a parallel study. In addition, they experienced less deterioration over time with respect to cognitive and global assessments. Beneficial effects of propentofylline were consistently demonstrated in the domains of cognitive and global function for both VaD populations; however, no treatment benefits could be demonstrated for activities of daily living, possibly due to factors relating to the study population/design, the lack of a validated test instrument for such patients, the caregiver-related phenomenon of “tutoring,” or the nature of the disease itself.

Effects of propentofylline on adenosine receptor activity in Chinese hamster ovary cell lines transfected with human A1, A2A, or A2B receptors and a luciferase reporter gene

Propentofylline is neuroprotective in vivo, but its mechanism of action is not completely understood. Previously, propentofylline was shown to block adenosine transport processes, to inhibit three adenosine receptor subtypes, and to inhibit cAMP phosphodiesterase. We tested the effect of propentofylline on adenosine receptor function in Chinese hamster ovary (CHO) cells transfected with human adenosine A1, A2A, or A2B receptors and a luciferase reporter gene under control of a promoter sequence containing several copies of the cAMP response element. We investigated the concentration-dependent inhibitory effects of propentofylline on cAMP phosphodiesterase, adenosine transport processes, and adenosine A1, A2A, and A2B receptors. At concentrations &gt;= 1 mM, propentofylline increased luciferase activity probably as a result of inhibition of cAMP phosphodiesterase. Inhibition of [3H]adenosine uptake by propentofylline was concentration dependent, with IC50 values of 37-39 µM for the three cell types. Agonist-activated adenosine A1 receptors were antagonized by 100 µM propentofylline, but inhibition of agonist-stimulated A2A or A2B receptors was not observed. In contrast, A1 and A2A receptor mediated effects of adenosine were enhanced by propentofylline at concentrations of 1 and 100 µM, respectively. These data indicate that the net effects of propentofylline in vivo will be dependent on the concentrations of propentofylline and adenosine available and on the subtypes of adenosine receptors, phosphodiesterases, and nucleoside transporters present.Key words: adenosine receptors, nucleoside transport, propentofylline.

Effect of propentofylline on hippocampal brain energy state and amyloid precursor protein concentration in a rat model of cerebral hypoperfusion.

An animal model of graded cerebral hypoperfusion achieved by way of 2- and 4-brain vessel occlusion (vo) was used to test the effect of chronic propentofylline (PPF) administration on hippocampal energy state and amyloid precursor protein (APP) concentration. For this purpose, forty adult rats were subjected to stepwise and permanent 2 vo and 4 vo and PPF in a dose of 25 mg/day per kilogram body weight was continuously administered intraperitoneally for 1 week or 3 weeks, respectively. During the final steady-state experiment arterial blood parameters and blood gases (mean arterial blood pressure, PO2, pCO2, pH, hematocrit, hemoglobin, body temperature) were measured. Brain tissue concentrations of adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine were measured in rat hippocampus by high-pressure liquid chromatography (HPLC) analysis; APP concentration was determined using Western blot techniques. In adult rat brain, long-term PPF treatment induced a striking increase in hippocampal ATP concentration which was paralleled by an enhancement of the ATP/ADP-ratio. Specifically, after 2 vo with 1 week of PPF treatment the ATP concentration in hippocampus was enhanced by 18% when compared with 2 vo without PPF treatment, whereas after 3 weeks PPF administration with 4 vo the concentration of ATP was enhanced by 31%. Furthermore, PPF reduced the tissue concentration of adenosine from 17.75 +/- 2.79 to 8.83 +/- 3.68 pmol/mg wet weight during 4 vo if compared with animals without PPF. In addition, the APP concentration was enhanced by 35% after 1 week PPF administration when compared with non PPF treated animals. In summary, the results demonstrated that chronic administration of PPF induced an enhancement in ATP concentration in adult rat hippocampus under conditions of long-term brain vessel occlusion. Interestingly, 1 week PPF seems to have a stimulating effect on APP which may act neuroprotectively. Thus, PPF may protect hippocampal neurons from chronic ischemic damage. In conclusion, PPF may have some beneficial effects and could be used in the treatment of patients with chronic cerebrovascular disorders or neurodegenerative diseases such as vascular dementia.

Effect of propentofylline on free radical generation during cerebral hypoxia in the newborn piglet

The present study tests the hypothesis that propentofylline, an adenosine re-uptake inhibitor, will reduce free radical generation during cerebral hypoxia. Ten newborn piglets were pretreated with propentofylline (10 mg/kg), five of which were subjected to hypoxia, while the other five were maintained at normoxia. Five untreated control piglets underwent the same conditions. Hypoxia was induced through a decrease in FiO 2 to 0.11 and documented biochemically by a decrease in ATP and phosphocreatine levels. Free radical formation in the cortex was detected directly using electron spin resonance spectroscopy with a spin trap technique. Results demonstrate that free radicals, corresponding to the alkoxyl radical, increased significantly following hypoxia, and that this increase was inhibited by pretreatment with propentofylline. Conjugated dienes, a lipid peroxidation product, also increased following hypoxia and were subsequently inhibited by propentofylline. The administration of propentofylline also significantly limited the hypoxia-induced decrease in tissue levels of ATP and phosphocreatine. These data demonstrate that pretreatment with propentofylline decreased free radical generation and lipid peroxidation as well as preserved high energy phosphates during cerebral hypoxia.

Propentofylline potentiates induced ischemic tolerance in gerbil hippocampal neurons via adenosine receptor.

The effect of propentofylline, an adenosine uptake inhibitor, on ischemic tolerance was investigated in the gerbil global ischemia model. Propentofylline was administered 24 hours after short preconditioning ischemia, and animals were subjected to 5-minute ischemia 24 hours thereafter. Propentofylline at a dose of 20 mg/kg intraperitoneally, but not at a dose of 10 mg/kg, significantly potentiated the protective effect of preconditioning ischemia in the CA1 hippocampal neurons. This effect was completely abolished by simultaneous administration of theophylline (20 mg/kg), an adenosine receptor blocker. This finding suggests the involvement of adenosine receptor for the development of ischemic tolerance.

Propentofylline enhancement of the actions of adenosine on neutrophil leukocytes

In agreement with previous results, activation of adenosine A 2 receptors was found to inhibit the exocytotic release of elastase and the oxidative burst induced by formyl-MetLeuPhe (fMLP) in human neutrophils. The adenosine analogue 5′- N-ethycarboxamidoadenosine (NECA) was more potent than adenosine (IC 50 14 vs 64 nM). The effects of adenosine and NECA were not influenced by the A 1-adenosine receptor selective antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 300 nM), but were abolished by the non-selective adenosine receptor antagonist 9-chloro-2-(2-furanyl)- 5,6-dihydro-[1,2,4]-triazolo [1,5]quinazolin-5-imine monomethanesulfonate (CGS 15943; 10 μM). Propentofylline per se caused a concentration-dependent inhibition of H 2O 2 production. At 100 μM, propentofylline significantly enhanced the effect of adenosine, but not that of NECA. This effect of propentofylline was shared by the known uptake inhibitor dipyridamole. Neither adenosine nor propentofylline altered fMLP-induced inositol-(1,4,5)-triphosphate (IP 3) formation. The results demonstrate that propentofylline can counteract neutrophil activation, at least partly by enhancing the action of adenosine through blocking its removal, and that the effect is exerted at a step after the initial receptor events.

Effect of propentofylline (HWA 285) on metabolic and functional recovery in the spinal cord after ischemia

The effect of propentofylline on metabolic and functional recovery in the spinal cord after ischemia and reperfusion was investigated. Ischemia was induced by abdominal aorta ligation below the left renal artery for 20 or 30 min. Propentofylline (1, 5, 10 and 20 mg/kg) was administered intravenously, immediately after reperfusion and the animals recovered for 4 days. Propentofylline at a dose of 1 mg/kg and 5 mg/kg had only a slight effect on energy metabolism recovery in the spinal cord and neurological recovery of hindlimbs. However, almost complete recovery of adenine nucleotides, lactate and glucose occurred after 20 min of ischemia in the animals treated with 10 or 20 mg/kg propentofylline. Partial metabolic recovery occurred even after 30 min of ischemia and 20 mg/kg propentofylline. The recovery of energy metabolism correlated closely with the recovery of neurological functions after ischemia and 4 days of survival.

Effect of propentofylline (HWA 285) on extracellular purines and excitatory amino acids in CA1 of rat hippocampus during transient ischaemia

1. The adenosine uptake blocker propentofylline (HWA 285) has previously been shown to protect hippocampal CA1 pyramidal cells from ischaemia-induced delayed neuronal death. The influence of propentofylline, on the extracellular concentrations of purines, aspartate and glutamate in the CA1 of the rat hippocampus during transient forebrain ischaemia was investigated. 2. Twenty min of ischaemia was induced by four-vessel occlusion in Wistar rats, extracellular compounds were sampled by use of microdialysis and EEG was recorded by a tungsten electrode attached to the dialysis probe. 3. Propentofylline (10 mg kg-1 i.p.) did not influence the basal levels of any of the compounds in the hippocampal dialysates. 4. The EEG became isoelectric within 20 s after induction of ischaemia. 5. Extracellular adenosine, inosine, hypoxanthine, aspartate and glutamate increased several fold during ischaemia and remained elevated during early reflow. Within 2 h of reperfusion the concentration of all compounds was normalized. Xanthine increased upon reperfusion and remained elevated after 2 h. 6. Propentofylline (10 mg kg-1 i.p.) administered 15 min before ischaemia significantly enhanced the ischaemia-evoked increase of adenosine but attenuated the increases of the other purine catabolites and of glutamate. 7. In separate in vitro experiments, propentofylline did not inhibit adenosine deaminase activity. 8. The present data show that propentofylline enhances extracellular adenosine and lowers extracellular glutamate in vivo during ischaemia. These findings may be important in relation to the neuroprotective properties of propentofylline.

Effect of xanthine derivatives on hippocampal long-term potentiation

The effect of the structurally similar xanthine derivatives, propentofylline, pentoxifylline and theophylline, on long-term potentiation (LTP) recorded in CA3 of hippocampal slices of guinea pigs was investigated. A concentration-dependent increase in the amplitude of the population spike of CA3 pyramidal neurons was evoked by bath application of propentofylline and theophylline with a threshold concentration of 10 μM. This increase returned to the control level after washout for 20–30 min. Propentofylline enhanced LTP with a threshold concentration of approximately 5 μM. Pentoxifylline and theophylline enhanced LTP with threshold concentrations between 100 and 1000 μM. The enhancement of LTP lasted for more than 30 min after washout of the xanthines. The effect of propentofylline (10 μM) on LTP was blocked either by the β-adrenoceptor antagonist propranolol (1 μM) or theophylline (10 μM). These results suggest that (i) the mode of action of propentofylline in enhancing LTP differs from that of pentoxifylline and theophylline and (ii) norepinephrine and adenosine are involved in the effect of propentofylline on LTP.

Effect of propentofylline on the biochemical lesion of the rat brain in aluminium-induced neurotoxicity

Acute and chronic administration of Al-gluconate (12.7% Al) at the concentration of 1 mg/kg produces edema in the rat brain, as reflected by the increase in water and Na+ content. The permeability for Evans blue is also increased, which indicates the opening of the blood-brain barrier. Higher concentrations of the Al-gluconate (10 mg/kg) change, in acute experiments, the pattern of energy metabolites in the rat brain toward a profile observed in a deep hypoxia. Chronic administration of a low concentration of Al-gluconate (1 mg/kg) increases the local utilization of glucose in 20 of 39 rat brain structures examined. This increase was particularly evident in the structures of the limbic system. Xanthine derivative propentofylline reverses the edema formation in acute and chronic experiments. Hypoxia-like changes in energy metabolism are also reversed by propentofylline. In preliminary experiments propentofylline also suppressed the increased utilization of glucose observed after administration of Al-gluconate. These results suggest that (i) the Al-gluconate model in rats can be used to study Al-neurotoxicity at a very low level of Al, and (ii) the xanthine derivative propentofylline can eventually be used to abolish the Al-neurotoxicity.

Effect of propentofylline on the GABA system of a rat brain

AbstractThe effect of propentofylline (HWA 285) [1‐(5′‐oxohexyl)‐3‐methyl‐7‐propylxanthine] on γ‐aminobutyric acid (GABA) levels and activities of 1‐glutamate decarboxylase (GAD), GABA transaminase (GABA‐T), and succinyl‐semialdehyde dehydrogenase (SSADH) in various rat brain regions (cortex, nucleus caudate, thalamus, hypothalamus, hippocampus, cerebellum, and brain stem) has been examined. Propentofylline (25 mg/kg body weight) 30 min after intraperitoneal injection induced a decrease of GAD and GABA‐T activity in all brain regions examined (significantly for GAD in cortex, caudate, thalamus, hypothalamus, and brain stem and for GABA‐T in cortex, caudate, thalamus, cerebellum, and brain stem). Under the same treatment, the GABA levels and SSADH activity were elevated in the regions examined (significantly for GABA in cortex, caudate, and thalamus and for SSADH in all brain regions). The results obtained indicate the existence of a multiple modulation of the GABA system functioning under propentofylline treatment.