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T W Stone

Publications and source records attributed to T W Stone.

At least 55 records · Page 3Linked to original sources
PubMed1999

Therapeutic and "dose-dependent" effect of repetitive microelectroshock induced by transcranial magnetic stimulation in Parkinson's disease.

Transcranial magnetic stimulation (TMS) has been used in the diagnosis of neurological lesions and has been introduced into the therapy of central nervous diseases. Lately it has been claimed that TMS would be useful not only in the treatment of depression, but also in relieving symptoms of Parkinson's disease. In this study, we sought evidence of the effect of repetitive TMS on the symptoms of Parkinson's disease, the dose dependency between the applied elecromagnetic field and the Parkinsonian symptoms, and the maintenance of the improvement. Forty-nine patients with Parkinson's disease were divided into four groups, each given one stimulus, repeated 30 times, once or twice a day ( approximately 0.34Tesla (T), approximately 0.57T, approximately 0.80T). Patients were followed for 3 months and assessed using two different parkinsonian scales: the graded clinical rating scale and Unified Parkinson Disability Rating Scale (UPDRS), and with a short-term memory test (Ziehen-Ranschburg word pair test). No effect was seen in the group treated with approximately 0.34T\30 stimuli once a day. In all of the groups receiving TMS twice a day, the parkinsonian scores were significantly decreased compared with that of baselines after 1 month of treatment. The greatest improvement in the hypokinesia was detected in the group treated with approximately 0.57T\30 stimuli twice a day (baseline total UPDRS: 30.62 +/- 15.23; 1 month after treatment: 17.08 +/- 7.04, P < 0.01; 3 months after treatment: 16.08 +/- 7.06, P < 0.01). A dose-dependent difference was observed between the two groups after 3 months. The total UPDRS in Group II ( approximately 0.34T\30 stimuli twice a day) significantly differed from Group III ( approximately 0.57T\30 stimuli twice a day; 22.43 +/- 8.87, 16.08 +/- 7.06, P < 0.05). The long-lasting improvement effect with TMS would seem to suggest it as an appropriate tool in the therapy of Parkinson's disease.

Analysis of Variance↗
PubMed1999

Occlusive responses to adenosine A1 receptor and muscarinic M2 receptor activation on hippocampal presynaptic terminals.

There is substantial evidence for an interaction between adenosine A1 and muscarinic M1/M3 receptors in some tissues, either at the level of the receptors themselves or at the associated transduction system. We have now addressed the question of whether there is a similar interaction between A1 and presynaptic M2 receptors in the hippocampus. The effects of cyclopentyladenosine (CPA) were studied alone or in combination with the M2 receptor agonist oxotremorine-M. The ability of both to depress synaptic transmission presynaptically at the concentrations used was confirmed using paired-pulse inhibition. When combined at a range of concentrations, the effects of the two agents were less than additive, suggesting that they are acting by a common transduction system. The results indicate that the modulatory, antagonistic effects of A1 adenosine receptors are exerted not only on postjunctional M1/M3 receptors but also at M2 presynaptic receptors.

Adenosine↗
PubMed1999

Actions of benzodiazepines and the benzodiazepine antagonist flumazenil may involve adenosine.

It has recently been reported that the benzodiazepine antagonist flumazenil (formerly Ro15-1788) has depressant actions of its own on hippocampal potentials. It is noted here that similar results were obtained over ten years earlier, in association with work showing that benzodiazepine agonists and antagonists could inhibit the uptake of adenosine. Such an action would lead to the extracellular accumulation of adenosine which, because of its ability to suppress transmitter release, could explain the recent results.

Adenosine↗
PubMed1999

Improvement in Parkinsonian symptoms after repetitive transcranial magnetic stimulation.

Transcranial magnetic stimulation has been used in the diagnosis of neurological lesions, but has also been shown to be useful in the treatment of depression. We have now examined the effect of applying transcranial magnetic stimulation daily for 10 days in a sample of 10 patients with Parkinson's disease in whom maximal benefit was being obtained from drug therapy. The subjects were followed for six months and showed significant improvements over this period when assessed using a range of measures. It is suggested that transcranial magnetic stimulation may be a valuable technique in the treatment or adjunct treatment of Parkinsonism, possibly by inducing changes in brain monoamine levels.

Aged↗
PubMed1999

Nucleotide and dinucleotide effects on rates of paroxysmal depolarising bursts in rat hippocampus.

Slices of rat hippocampus can be induces to generate spontaneous interictal-like bursts of action potentials when perfused with a with a medium containing no added magnesium and 4-aminopyridine (4AP). The frequency of these bursts is depressed by adenosine 5'triphosphate (ATP) and this effect can be prevented by cyclopentyltheophylline but not by adenosine deaminase. AMP (50 microM) had a similar action to reduce discharge rate. At 10 microM, adenosine, diadenosine tetraphosphate and diadenosine pentaphosphate all decreased the burst frequency. Adenosine deaminase (0.2 U ml-1) totally annulled the inhibition of epileptiform activity produced by 10 microM adenosine but reduced only the later components of the inhibition by 10 microM diadenosine tetraphosphate and diadenosine pentaphosphate. Cyclopentyltheophylline prevented the depression of burst discharges by diadenosine tetraphosphate. 5'-adenylic acid deaminase (AMPPase) did not significantly alter the discharge rate over the 10 min superfusion period used for drum application but did prevent the depressant effect of AMP and ATP. AMP deaminase did not prevent the inhibitory effects of diadenosine tetraphosphate. The results suggests that in the CA3 region of the hippocampus, diadenosine tertraphosphate and diadenosine pentaphosphate act partly by stimulating xanthine sensitive receptors directly and partly via metabolism to adenosine, and that AMP may be responsible for the inhibitory effects of ATP on epileptiform activity.

AMP Deaminase↗
PubMed1999

Oxidative stress as a mechanism for quinolinic acid-induced hippocampal damage: protection by melatonin and deprenyl.

1. There are differences between the excitotoxic actions of quinolinic acid and N-methyl-D-aspartate (NMDA) which suggest that quinolinic acid may act by mechanisms additional to the activation of NMDA receptors. The present study was designed to examine the effect of a potent antioxidant, melatonin, and the potential neuroprotectant, deprenyl, as inhibitors of quinolinic acid-induced brain damage. Injections were made into the hippocampus of anaesthetized rats, which were allowed to recover before the brains were taken for histology and the counting of surviving neurones. 2. Quinolinic acid (120 nmols) induced damage to the pyramidal cell layer, which was prevented by the co-administration of melatonin (5 nmols locally plus 2x20 mg kg(-1) i.p.). This protective effect was not prevented by the melatonin receptor blocker luzindole. Neuronal damage produced by NMDA (120 nmols) was not prevented by melatonin. 3. Quinolinic acid increased the formation of lipid peroxidation products from hippocampal tissue and this effect was prevented by melatonin. 4. Deprenyl also prevented quinolinic acid-induced damage at a dose of 50 nmols but not 10 nmols plus 2x1.0 mg kg(-1) i.p. The non-selective monoamine oxidase inhibitor nialamide (10 and 50 nmols plus 2x25 mg kg(-1)) did not afford protection. 5. The results suggest that quinolinic acid-induced neuronal damage can be prevented by a receptor-independent action of melatonin and deprenyl, agents which can act as a potent free radical scavenger and can increase the activity of endogenous antioxidant enzymes respectively. This suggests that free radical formation contributes significantly to quinolinic acid-induced damage in vivo.

Animals↗
PubMed1998

Interaction between adenosine A1 and A2 receptor-mediated responses in the rat hippocampus in vitro.

Previous work has been carried out on the effects of adenosine on transmitter release and on the excitability of postsynaptic neurones, but little is known about the effects of adenosine on the coupling between the two. In this study, we examine the effects of specific adenosine receptor agonists and antagonists on the population excitatory postsynaptic potential (population EPSP) slope, the population spike amplitude, and the relationship between the two (E-S coupling) in the CA1 area of rat hippocampus. Activation of adenosine A1 receptors by adenosine or the selective agonist N6-cyclopentyladenosine resulted in a decrease of the population spike amplitude by a greater extent than could be accounted for by the decrease in population EPSP slope, resulting in a dissociation in the E-S relationship, reflected as a right-shift in the E-S curve. Activation of adenosine A2A receptors by the selective agonist 2-p-(2-carboxyethy)phenethylamino-5'-N-ethylcarboxamidoadeno sine (CGS 21680), or blockade by antagonists ZM 241385 and CP 66713 had no effect on evoked responses. However, when both adenosine A1 and A2A receptors were activated at the same time, a significant attenuation of the inhibitory effects of N6-cyclopentyladenosine on population spike amplitude was observed, resulting in a left-shift in the E-S curve. Intracellular recording indicated that N6-cyclopentyladenosine raised the threshold for spike induction by pulses of depolarising current, even at a concentration which did not produce hyperpolarisation of the neurone. At 30 nM, CGS 21680 prevented this effect of N6-cyclopentyladenosine, and this apparent antagonism was prevented by the A2A receptor antagonist ZM 241385. The results show that adenosine A1 receptors change the coupling between presynaptic transmitter release and postsynaptic cell firing, and that this effect is attenuated by A2A receptor activation.

Adenosine↗
PubMed1998

Protection against hippocampal kainate excitotoxicity by intracerebral administration of an adenosine A2A receptor antagonist.

We have previously shown that the peripheral administration of an A2A receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680) protected the hippocampus against kainate-induced excitotoxicity. The present study utilises the intrahippocampal route to further investigate CGS 21680-mediated protection as well as examining the role of adenosine and both A1 and A2A receptors in kainate-induced excitotoxicity. Injections were made directly into the hippocampus of anaesthetised male Wistar rats. Following surgery and the administration of 0.25 nmol kainate in 1 microl of solution, the animals were left to recover for seven days before perfusion and brain slicing. Haematoxylin and eosin staining revealed substantial damage to the CA3 region. Co-administration of the A2A receptor agonist CGS 21680 over a range of doses did not protect the region to any degree. Similarly neither the A1 receptor agonist R-phenylisopropyladenosine (R-PIA), nor adenosine itself reduced kainate-induced damage. The intrahippocampal injection of the selective A2A receptor antagonist, 4-(2-[7-amino-2-¿2-furyl¿¿1,2, 4¿triazolo¿2,3-a¿¿1,3,5¿triazin-5-yl-amino]ethyl)phenol (ZM241385) however, significantly decreased kainate damage to the CA3 region. These results show that adenosine A2A receptor-induced protection is most likely to be mediated peripherally and is probably not due to activation of A2A receptors within the hippocampus. The lack of protection observed with either R-PIA or adenosine may be due to an inhibitory action of the A2A receptor on the neuroprotective A1 receptor. Importantly, this study also questions the role of endogenously released adenosine in protecting the hippocampus from excitotoxic damage.

Adenosine↗
PubMed1998

Nitric oxide synthase inhibitors L-NAME and 7-nitroindazole protect rat hippocampus against kainate-induced excitotoxicity.

The role of nitric oxide in cerebral insults remains controversial. While numerous studies have used models of ischaemia and hypoxia, few have examined nitric oxide in the kainate model of excitotoxicity. Kainate (10 mg/kg) was administered to rats via the intraperitoneal (i.p.) route to induce submaximal damage to the CA1, CA2 and CA3a regions of the hippocampus after 7 days. Systemic injections of the nitric oxide synthase (NOS) inhibitors N(G)-nitro-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NI), both at a dose of 5 mg/kg, reduced cell death in all three regions. As 7-NI selectively inhibits the neuronal form of NOS, this study suggests that nitric oxide produced from a neuronal and not epithelial source may contribute to neuronal damage in this model.

Analysis of Variance↗
PubMed1998

Comparison of an adenosine A1 receptor agonist and antagonist on the rat EEG.

The effects of the selective adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA; 1 and 0.1 mg/kg, i.p.) and the A1 selective antagonist 8-cyclopentyl-1,3-dipropylxanthine (CPX) have been examined on the electroencephalogram (EEG) of intact rats. From four EEG leads the EEG signal was subjected to Fast Fourier Transform and analysed both in narrow (0.01629638 Hz) and wide frequency bands. CPA tended to increase EEG power at low frequencies, and in several of the narrow frequency bands significantly shifted peak frequencies to lower values. The agonist also increased peak power in some frequency bands. The results are consistent with the view that A1 adenosine receptors mediate a generally depressant effect on neuronal activity in most brain regions, but may increase activity in areas with low resting rates of firing. The modest elevation of wave power by CPX indicates a limited control by resting endogenous adenosine, which is greatest in areas of highest activity, consistent with adenosine release being related to neuronal activity.

Adenosine↗
PubMed1998

Adenosine receptor-mediated inhibition of neurite outgrowth from cultured sensory neurons is via an A1 receptor and is reduced by nerve growth factor.

Adult dorsal root ganglion (DRG) cells are capable of neurite outgrowth in vitro as well as in vivo. We have investigated the influence of adenosine and analogs on the potential of cultured adult mouse DRG neurons to produce neurites in the presence and absence of nerve growth factor (NGF) which is a well-established trophic factor of sympathetic and sensory neurons during development. It is also believed to be essential for the maintenance or regulation of differentiated phenotypes of mature peripheral neurons. The results demonstrate that DRG neurons are modulated by purines in the absence of exogenous NGF. The addition of 100 microM adenosine to neurite-bearing DRG neurons inhibited neurite growth by 47% after 2-day exposures in vitro and by 50% after 5 days whereas in the presence of NGF this inhibition was reduced to 28% and 32%, respectively. 100 microM CHA (N(6)-cyclohexyl adenosine) alone reduced neurite total length by 47% after 2 days and by 48% after 5 days. 100 microM CGS21680 (2-p-(2-carboxyethyl) phenethylamino-5'-N-ethylcarboxamido adenosine hydrochloride) alone also reduced neurite total length by 46% after 2 days and by 58% after 5 days which was reduced to 21% and 37%, respectively, in the presence of 100 ng/ml NGF. The antagonist studies revealed that activation of A1 adenosine receptors is primarily responsible for the effect on neuritogenesis since the inclusion of 1 or 10 microM CPX (8-cyclopentyl-1,3-dipropyl xanthine) fully prevented the inhibitory activity of adenosine or CHA whereas DMPX (3,7-dimethyl-1-propargyl xanthine) did not prevent inhibition by CHA. The converse experiment yielded the consistent result that inhibition by the A2 receptor agonist CGS21680 could be prevented by CPX, but not DMPX.

Animals↗
PubMed1998

Potentiation of muscimol-induced long-term depression by benzodiazepines and prevention or reversal by pregnenolone sulfate.

We have recently reported a new protocol for inducing long-term depression through activation of GABAA receptors in the hippocampal slices. This long-term depression is reversed by bicuculline and potentiated by neurosteroids such as alphaxalone. It was also shown that glutamate receptor activity or extracellular calcium are not involved in the induction of this type of long-term depression. The present study investigated the possible relation between muscimol-induced long-term depression and barbiturates/benzodiazepine-induced amnesia and attempts to determine the possible effect of pregnenolone sulfate on muscimol-induced long-term depression. Extracellular recordings were made in the CA1 pyramidal cell layer of rat hippocampal slices following orthodromic stimulation of Schaffer collateral fibres in stratum radiatum (0.01 Hz). It was observed that pentobarbital, benzodiazepines and pregnanolone at concentrations that did not have any effect themselves on the population spike, potentiate the ability of muscimol to induce long-term depression. In addition to this, the long-term depression was either blocked or reversed by pregnenolone sulfate at concentrations (10 microM) where pregnenolone sulfate did not induce any multiple burst or increase of spike size. The results suggest that the potentiation of this type of long-term depression by benzodiazepines and barbiturates can explain the main adverse effect of these drugs, amnesia and cognitive impairment. Moreover, the prevention or reversal of this type of long-term depression by pregnenolone sulfate, may suggest a clinical application of this agent in the management of amnesia or dementia.

Amnesia↗
PubMed1998

Tolbutamide blocks postsynaptic but not presynaptic effects of adenosine on hippocampal CA1 neurones.

Extracellular recording in the CA1 pyramidal cell layer of rat hippocampal slices was used to examine the effect of the ATP-sensitive potassium channel blocker tolbutamide and the channel opener levcromakalim on responses to adenosine. Tolbutamide 1 mM blocked the inhibitory effect of adenosine on the size of orthodromic population spikes but had no effect on the inhibitory action of adenosine on field EPSPs. Tolbutamide also blocked the suppression by adenosine of repetitive antidromic spikes induced in calcium-free media with high magnesium but did not prevent the effects of baclofen. Levcromakalim 100 microM potentiated inhibitory effect of adenosine, but not baclofen, on orthodromic population spikes. The results show that at postsynaptic, but not presynaptic, sites adenosine may activate an ATP-sensitive potassium channel.

Adenosine↗
PubMed1998

Increased expression of dendritic mRNA following the induction of long-term potentiation.

A small number of mRNAs, including Ca2+/calmodulin-dependent protein kinase II alpha-subunit (CamKIIalpha) mRNA and microtubule-associated protein 2 (MAP2) mRNA, are present in the dendrites of neurones as well as in the cell bodies. We show here that the induction of long-term potentiation (LTP) in the hippocampal perforant path/granule cell synapses in anaesthetised rats is associated with increased levels of CamKIIalpha mRNA and MAP2 mRNA in the granule cell dendrites after 2 h. Similarly, induction of LTP in the Schaffer collateral/CA1 pyramidal cell synapses in hippocampal slices maintained in vitro also results in elevated dendritic levels of CamKIIalpha mRNA and MAP2 mRNA 2 h later. In both models, the levels of various other mRNA species restricted to the cell body region were unaffected by the induction of LTP. Increased expression of dendritic CamKIIalpha mRNA and MAP2 mRNA appears to be a general feature of hippocampal plasticity, since it occurs following LTP induction in both the dentate gyrus and the CA1 region. The elevation of mRNA levels in a restricted region close to the afferent synapses would allow a highly-localised enhancement of the synthesis of the corresponding proteins, providing an elegant mechanism for protein-synthesis-dependent synaptic plasticity to maintain a high degree of anatomical specificity.

Animals↗
PubMed1998

Protection by an adenosine analogue against kainate-induced extrahippocampal neuropathology.

1. The glutamate analogue kainic acid produces neuronal damage in the central nervous system. We have reported that analogues of adenosine, such as R-N6-phenylisopropyladenosine (R-PIA) can, at doses as low as 10 microg/kg IP, prevent the hippocampal damage that follows the systemic administration of kainate. The present work was designed to examine purine protection against kainate in extrahippocampal regions by using histological methods. 2. The results show that R-PIA, at a dose of 25 microg/kg IP in rats, can protect against the neuronal damage caused by kainate in the basolateral amygdaloid nuclei, the pyriform cortex and around the rhinal fissure. This protection could be prevented by the simultaneous administration of the A1 adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine, confirming that the protection involved adenosine A1 receptors. No protection was observed in the posterior amygdaloid nuclei or the entorhinal cortex, suggesting the absence of relevant adenosine receptors or a different mechanism of excitotoxicity.

Adenosine↗
PubMed1998

Protection against kainate-induced excitotoxicity by adenosine A2A receptor agonists and antagonists.

The neuroprotective role of adenosine receptor agonists in various models of ischaemia and neuronal excitotoxicity has been attributed to adenosine A1 receptor activation. In this study we examine the role of the A2A receptor in the kainate model of excitotoxicity. Kainate (10 mg/kg) was administered systemically 10 min after the intraperitoneal injection of adenosine analogues. The A2A agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS21680) protected the hippocampus at concentrations of 0.1 and 0.01 mg/kg, but not at 2 microg/kg. The addition of the centrally acting adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine partially reduced protection only in the CA3a region, suggesting that only a small proportion of the protection was attributable to the A1 receptor. A less potent A2A agonist, N6-[2-(3,5-dimethyoxyphenyl)-2-(2-methylphenyl)-ethyl]adenosine (1 mg/kg), provided only partial protection against kainate. 4-(2-[7-Amino-2-[2-furyl][1,2,4]triazolo[2,3-a][1,3,5]triazin-5-yl -amino]ethyl)phenol, a selective A2A antagonist, also showed protection against kainate-induced neuronal death, when administered alone or in combination with CGS21680. These results show that adenosine A2A receptor activation is protective against excitotoxicity. The protection is largely independent of A, receptor activation or blockade.

Adenosine↗