Biomedical subjects

K A Rudolphi

Publications and source records attributed to K A Rudolphi.

14 recordsLinked to original sources

PubMed1998

[New pharmacologic aspects in the neurologic profile of propentofylline (Karsivan ad us. vet.)].

Propentofylline (Karsivan, Hoechst Roussel Vet) is a selective inhibitor of adenosine transport and phosphodiesterase. For several years it has been well established in the geriatric therapy of the dog improving hemodynamics in cerebral and peripheral compartments. In human medicine clinical development of this pharmaceutical has already entered an advanced stage for the long-term therapy of patients with Alzheimer's disease and vascular dementia. In the brains of senile dogs and in human patients suffering from Alzheimer's disease comparable neuropathological findings can be made. In senile dogs a distinctive correlation exists between the quantity of beta-amyloid accumulation and the degree of dementia. The extension of knowledge by clinical studies in humans and by experimental studies in animals may contribute to a deeper understanding of therapeutical approaches of cognitive dysfunction in the old dog. The xanthine derivative propentofylline [1-(5'-oxohexyl)-3-methyl-7-propylxanthine] directly interfers with the neurodegenerative process and reduces the extent of damage to brain structures. In experimental models of vascular dementia and/or Alzheimer's disease it improves cognitive functions, inhibits inflammatory processes as well as excessive activation of microglia, formation of free radicals, cytocines and abnormal amyloid precursor proteins (APP). It stimulates synthesis and liberation of nerve growth factor (NGF) and reduces ischemic damage to the brain. In clinical studies in humans it improved cognitive functions as well as global functions and the ability to cope with tasks of routine daily life in patients suffering from Alzheimer's disease and vascular dementia.

Adenosine↗

PubMed1997

Modulation of neuronal and glial cell function by adenosine and neuroprotection in vascular dementia.

Dementia is one of the major medical challenges in the industrialized countries. An increasing number of demented patients shows ischemic brain lesions. One strategy to treat dementia could be the reinforcement of the multifarious neuroprotective actions of the endogenous cell modulator adenosine. This involves the modulation of neuronal and glial cell functions. Adenosine appears to raise the threshold for the initiation of the pathophysiological cascade of ischemic neuronal death by counteracting ischemic membrane depolarization and the successive disturbance of intracellular Ca2+ homeostasis. When this threshold is overcome, adenosine seems to stimulate astrocyte differentiation and reinforce important protective astrocyte functions, e.g., synthesis and release of neurotrophic factors such as NGF and the clearance of abnormal neurotoxic levels of K+ and glutamate from the extracellular space. Propentofylline, a combined inhibitor of adenosine reuptake and cAMP phosphodiesterases, reinforces the actions of endogenous adenosine and cAMP. One important action of propentofylline is the inhibition of potentially neurotoxic functions of activated microglia (free radical formation and transformation into brain macrophages). Such drugs may help to inhibit the progressive neurodegenerative process in dementia.

Adenosine↗

PubMed1994

Synthesis, resolution, and SAR of (+/-)-2-amino-N-methyl-alpha-(3-methyl-2-thienyl)benzeneethanamine++ + and related analogs as noncompetitive NMDA antagonists with neuroprotective properties.

The preparation and structure-activity relationships of a series of 2-amino-alpha-thienylbenzeneethanamines are described. From this work, (+/-)-2-amino-N-methyl-alpha-(3-methyl-2-thienyl)-benzeneethanamine++ + (3a) and the homologous N-ethyl analog 3b emerged as novel noncompetitive NMDA antagonists with neuroprotective properties. Optical resolution of 3a and X-ray crystallography of (+)3a were performed. The racemate and enantiomers were evaluated for neuroprotective properties in models of ischemia-induced hippocampal damage (gerbil) and cerebral focal ischemia (rat). Pretreatment with 3a, (+)3a, or (-)3a significantly reduced ischemia-induced CA1 hippocampal damage. Posttreatment with 3a afforded a lower degree of neuroprotection. A highly significant reduction in infarct volume was observed with 3a in the cerebral focal ischemia model, with only weak positive effects being displayed by (+)3a. Dose-limiting side effects were associated with all three compounds in this model. In summary, the results demonstrate the utility of noncompetitive NMDA antagonists as neuroprotective agents for ischemia-induced neurodegeneration.

Aniline Compounds↗

PubMed1994

Antiischemic effects of propentofylline (HWA 285) against focal cerebral infarction in rats.

The effects of the xanthine derivative propentofylline (HWA 285), an inhibitor of adenosine transport, on ischemic brain damage have been evaluated in a model of permanent middle cerebral artery (MCA) occlusion in rats. During the postischemic survival period of 24 h, the animals were subjected to neurological and behavioral observations and then sacrificed to assess the extent of ischemic tissue damage by tetrazolium chloride. Posttreatment with propentofylline (0.01, 0.05 or 0.1 mg/kg/min, continuous i.v. infusion) initiated 15 min following MCA occlusion, produced significant reductions in infarct volumes; the highest being the most effective (reduction by 39%; P < 0.005) and improved the neurological symptoms when compared with an untreated control group. In contrast to other antiischemic agents, such as glutamate receptor antagonists, the drug induced no behavioral disturbances. This study indicates that propentofylline may provide neuroprotective effect against ischemic brain damage following stroke without negative behavioral side effects.

Adenosine↗

PubMed1994

Propentosylline depresses amyloid and Alzheimer's CSF microglial antigens after ischaemia.

In the gerbil hippocampus activated microglial antigens are intensely stained by cerebrospinal fluid from patients with Alzheimer's disease (AD-CSF), OX18 and the amyloid precursor protein (beta-APP) up to 14 days after ischaemia. Propentosylline (PPF), which facilitates the adenosine A2 receptor action, has been shown to be neuroprotective, to depress O2- radical formation in macrophages and to interfere with the generation of phagocytotic macrophages from cultivated microglial cells. In this report we tested in ischaemic gerbils whether PPF treatment influences the potential neurotoxic properties of microglia. Daily post-treatment with PPF, started 24 h after ischaemia, depressed the immunostaining of activated microglia by AD-CSF, OX18 and APP in the hippocampus. Thus, PPF may protect against microglia-related brain damage.

Alzheimer Disease↗

PubMed1994

Propentofylline: a nucleoside transport inhibitor with neuroprotective effects in cerebral ischemia.

1. Adenosine is an endogenous neuroprotective agent; stimulation of A1 receptors decreases excitatory amino acid neurotransmission and stimulation of A2 receptors inhibits platelet and neutrophil activation and promotes vasodilation. 2. Post-ischemic administration of propentofylline (HWA 285) reduces neuronal damage in gerbils and improves glucose metabolism in all regions of brain in acute stroke patients. 3. Propentofylline inhibits the transport of adenosine into cultured cells and increases extracellular adenosine concentrations in ischemic brain. Thus, enhanced stimulation of adenosine receptors may account for some of the neuroprotective effects of this compound. 4. Propentofylline inhibits free radical production by cultivated microglia cells, stimulates nerve growth factor production and inhibits cAMP-phosphodiesterase activity. These effects may also be important for neuroprotection.

Adenosine↗

PubMed1992

Neuroprotective role of adenosine in cerebral ischaemia.

Several lines of evidence suggest that adenosine may be an endogenous protective agent in cerebral ischaemia. Adenosine is normally present in the extracellular fluid in most tissues of the body, including the brain, and its level increases dramatically following hypoxia or ischaemia. The rate of adenosine production is enhanced when the energy demand is larger than the rate of energy supply. Adenosine acts on specific receptors that are present in most cells in the body and that produce cellular effects that tend to antagonize a number of pathological events thought to be instrumental for ischaemic nerve cell death. Karl Rudolphi and colleagues review evidence for the neuroprotective potential of adenosine and indicate some targets for drug development.

Adenosine↗

PubMed1992

Adenosine and brain ischemia.

Recent experimental data indicate a probable role of adenosine as an endogenous neuroprotective substance in brain ischemia. This nucleoside is rapidly formed during ischemia as a result of intracellular breakdown of ATP and it is subsequently transported into the extracellular space. With use of microdialysis and other techniques, a massive increase of interstitial adenosine has been measured during ischemia in different brain areas. Adenosine acts through two subtypes of receptors, A1 and A2, which are located on neurons, glial cells, blood vessels, platelets, and leukocytes and are linked via G-proteins to different effector systems such as adenylate cyclase and membrane ion channels. There is a very high density of A1-receptors in the hippocampus, an area with specific vulnerability to ischemia. In different in vivo and in vitro models of brain ischemia, the pharmacological manipulation of the adenosine system by adenosine receptor antagonists tended to aggravate ischemic brain damage, whereas the reinforcement of adenosine action by receptor agonists or inhibitors of cellular reuptake and inactivation showed neuroprotection. The up-regulation of adenosine A1-receptor number and affinity by chronic preadministration of the competitive antagonist caffeine also attenuated ischemic brain damage. The mechanisms underlying the neuroprotective effects of adenosine seem to involve both types of adenosine receptors, A1 and A2, but the A1-mediated pre- and postsynaptic neuromodulation may be of special importance. By inhibiting neuronal Ca2+ influx, adenosine counteracts the presynaptic release of the potentially excitotoxic neurotransmitters glutamate and aspartate, which may impair intracellular Ca2+ homeostasis via metabotrophic glutamate receptors or induce uncontrolled membrane depolarization via ion channel-linked glutamate receptors, especially of the N-methyl-D-aspartate (NMDA) type. In addition, adenosine directly stabilizes the neuronal membrane potential by increasing the conductance for K+ and Cl- ions, thereby counteracting excessive membrane depolarization. The latter triggers a number of pathological events including blockade of voltage-sensitive K+ currents, increase of NMDA receptor-mediated Ca2+ influx, and presumably also impairment of glutamate uptake by astrocytes. In the way of a vicious cycle, all these factors again tend to enhance extracellular glutamate levels and membrane depolarization, finally leading to cytotoxic calcium loading and neuronal cell death. In addition to its important neuromodulatory effects, which tend to reduce energy demand of the brain, adenosine acting via A2-receptors in brain vessels, platelets, and neutrophilic granulocytes may improve the cerebral microcirculation and thus oxygen and substrate supply to the tissue. There is evidence that the functional state of adenosine receptors is impaired during ischemia, limiting the time window of the adenosine action.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine↗

PubMed1990

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.

Adenosine Deaminase↗

PubMed1990

Preclinical anticonvulsant and neuroprotective profile of 8319, a non-competitive NMDA antagonist.

8319, ((+-)-2-Amino-N-ethyl-alpha-(3-methyl-2-thienyl)benzeneethanamine 2HCl), is a novel compound with the profile of a non-competitive NMDA antagonist. The compound displaced [3H] TCP with high affinity (IC50 = 43 nM), but was inactive at the NMDA, benzodiazepine and GABA sites; in vivo, 8319 showed good efficacy as an anticonvulsant and potential neuroprotective agent. It blocked seizures induced by NMDLA, supramaximal electroshock, pentylenetetrazol (PTZ), picrotoxin, and thiosemicarbazide with ED50's of 1-20 mg/kg ip. As a neuroprotective agent, 8319 (30-100 mg/kg sc) prevented the death of dorsal hippocampal pyramidal cells induced by direct injection of 20 nmol NMDA. At 15 mg/kg ip, the compound was also effective against hippocampal neuronal necrosis induced via bilateral occlusion of the carotid arteries in gerbils. In summary, 8319 is a noncompetitive NMDA antagonist with good anticonvulsant activity and may possess neuroprotective properties useful in the treatment of brain ischemia.

Aniline Compounds↗

PubMed1989

Ischaemic damage in gerbil hippocampus is reduced following upregulation of adenosine (A1) receptors by caffeine treatment.

We have used the fact that long-term caffeine treatment upregulates the adenosine receptors, to examine the role of adenosine in ischaemia. Four-week oral treatment with caffeine (0.2% in drinking water) caused a significant (10-17%) increase in the binding of the adenosine A1-receptor ligand [3H]cyclohexyl-adenosine (CHA) to several brain regions, including the hippocampal CA1 area, in Mongolian gerbils. Animals subjected to such treatment exhibited significantly less neuronal damage in the CA1 region following 5 min bilateral carotid occlusion than did control animals (50% of the caffeine-treated animals showed no damage at all compared to 11% in the control group). Our findings provide further evidence for a protective role of endogenous adenosine during ischaemia.

Administration, Oral↗

PubMed1988

Effects of adenosine and its analogues on porcine basilar arteries: are only A2 receptors involved?

The aim of this study was to test the effect of adenosine and four of its analogues, 5'-(N-ethyl)carboxamidoadenosine (NECA), 2-chloroadenosine (2-CADO), L-phenylisopropyladenosine (L-PIA), and N6-cyclohexyl-adenosine (CHA), on prostaglandin (PG) F2 alpha-constricted pig basilar arteries, and from their rank order of potency determine the receptor type involved. The order of potency for the relaxation of the PGF2 alpha constriction was NECA greater than adenosine, 2-CADO greater than L-PIA greater than CHA, which is in keeping with the A2 receptor subtype. The study also investigated the effects of a known adenosine antagonist, namely, the xanthine derivative 8-phenyltheophylline, which at concentrations having no intrinsic effect (10(-8) and 10(-7) M) produced a significant shift to the right only for the NECA dose-response curve.

2-Chloroadenosine↗

PubMed1987

Effect of theophylline on ischemically induced hippocampal damage in Mongolian gerbils: a behavioral and histopathological study.

We investigated the influence of the adenosine antagonist theophylline on the degree of hippocampal cell damage in the Mongolian gerbil following brief periods of forebrain ischemia. Male gerbils were randomly divided into nine groups. Ten minutes before surgery, four groups, which were later subjected to 1, 2, 3, or 5 min of bilateral carotid occlusion under halothane anesthesia, received theophylline (30 mg/kg, p.o.). Four groups served as nontreated ischemic controls; the ninth group was used to measure theophylline serum concentration. Neurological symptoms were classified by using a behavioral score. Fourteen days after ischemia, the brains were removed, and the hippocampus was histologically examined "blind" for the degree of cell damage in the CA1 sector, which was expressed as a semiquantitative histopathological score. There were no behavioral or histological abnormalities in either the control or theophylline group with 1 min of ischemia. With increasing duration of ischemia, the neurological symptoms worsened and the number of necrotic pyramidal cells increased significantly. The pretreatment with theophylline only moderately aggravated the neurological symptoms, whereas it enhanced the ischemic cell damage significantly. The results are discussed with respect to recent findings that theophylline may block putatively protective effects of endogenous adenosine, whose concentration in the brain is known to rise significantly during ischemia.

Adenosine↗

PubMedDate not supplied

Modulation of nerve and glial function by adenosine--role in the development of ischemic damage.

Adenosine is released during brain ischemia and provides neuroprotection by actions on nerve and glial cells. Activation of the adenosine A1 receptor enhances the K+ and Cl- conductance in neurons, leading to membrane hyperpolarization and postsynaptic reduction of neuronal Ca2+ influx through voltage- and NMDA receptor-dependent channels. In addition adenosine A1 receptor activation decreases excitatory amino acid release, possibly via inhibition of N- and P-type Ca2+ channels. The A1 and A2 receptors, coupled to Gi/G(o) and Gs proteins respectively, often co-exist and interact with the phospholipase C-dependent activation of the protein kinase C and the adenylyl cyclase. Activation of the A1 receptor may mimic metabotropic receptor stimulation in activating intracellular Ca2+ mobilization and PKC. A2 receptor mediated cAMP formation is depressed by high intracellular Ca2+ but enhanced by PKC activation. By modulating these metabolic signaling events, adenosine may influence acute cell functions, gene transcription and sustained changes of nerve and glial cells relevant for the development of ischemic damage. The neuroprotective adenosine effect seems to be amplified by treatment with propentofylline, which enhances adenosine release, influences the balance between A1 and A2 receptor mediated actions, depresses the free radical formation in activated microglia and influences astrocyte reactions.

Adenosine↗