Multidisciplinary, multicomponent interventions to reduce frailty among older persons in residents of residential care facilities: a scoping review.

BACKGROUND: Frailty reduction and reversal have been addressed successfully among older populations within community settings. However, these findings may not be applicable to residential care settings, largely due to the complex and multidimensional nature of the condition. Relatively, few attempts at frailty prevention exist in residential settings. This review aims to identify and describe best practice models of care for addressing frailty among older populations in residential care settings. This research also sets out to explore the impact of multidisciplinary health service delivery models on health outcomes such as mortality, hospitalisations, quality of life, falls and frailty. METHODS: A scoping review of the literature was conducted to address the project objectives. Reference lists of included studies, bibliographic databases and the grey literature were systematically searched for literature reporting multidisciplinary, multidimensional models of care for frailty. RESULTS: The scoping review found no interventions that met the inclusion criteria. Of the 704 articles screened, 664 were excluded as not relevant. Forty articles were fully assessed, and while no eligible studies were found, relevant data were extracted from 10 near-eligible studies that reported single disciplines or single dimensions rather than a model of care. The physical, nutritional, medicinal, social and cognitive aspects of the near eligible studies have been discussed as playing a key role in frailty reduction or prevention care models. CONCLUSION: This review has identified a paucity of interventions for addressing and reducing frailty in residential care settings. High-quality studies investigating novel models of care for addressing frailty in residential care facilities are required to address this knowledge gap. Similarly, there is a need to develop and validate appropriate screening and assessment tools for frailty in residential care populations. Health service providers and policy-makers should also increase their awareness of frailty as a dynamic and reversible condition. While age is a non-modifiable predictor of frailty, addressing modifiable factors through comprehensive care models may help manage and prevent the physical, social and financial impacts of frailty in the ageing population.

Health-related quality of life in rural cancer survivors compared with their urban counterparts: a systematic review.

PURPOSE: We conducted a systematic review to describe health-related quality of life (HRQOL) in rural cancer survivors (RCS), and compare HRQOL between RCS and urban cancer survivors (UCS). METHOD: We searched Medline, Embase, CINAHL Plus, and PsycINFO for studies with HRQOL in adult cancer survivors living in rural, regional, remote, and urban areas, who had completed definitive primary cancer treatment, without evidence of residual disease. Where available, we used normative and clinically important values to ascribe meaning to HRQOL data. FINDINGS: Fifteen studies (16 papers) were included. Most were from the US (n = 8) and reported on breast cancer survivors (n = 9). Six HRQOL instruments, collecting data across 16 domains, were used. Three instruments were specific to the survivorship phase. Normative and clinical data were available for 12 studies. Compared with normative populations, RCS had clinically worse physical HRQOL (6/12 studies), better social/family (5/7), and functional (3/6) HRQOL, and there were no differences in emotional or/mental HRQOL (9/12). In six studies with rural-urban comparator groups and normative and clinically important data, RCS and UCS had clinically worse physical (3/6 and 2/6, respectively) and better social/family (3/4 and 2/4 studies, respectively) HRQOL than normative populations. Functional HRQOL was better in RCS (2/4 studies) than UCS and normative populations. In 3/6 studies, there were no clinical differences in emotional or/mental HRQOL between RCS, UCS, and normative populations. CONCLUSION: Overall, HRQOL is not clearly better or worse in RCS than UCS. Future research should include different tumor types, rural residents, and survivorship-specific HRQOL instruments.

Parent use of complementary medicine remedies and services for the management of respiratory tract infection in children: a qualitative study.

BACKGROUND: The use of complementary and alternative medicine (CAM) is increasing globally, in both adults and children. A common condition where CAM is used in children is acute respiratory tract infection (ARTI). However, limited information exists regarding specific CAM modalities used in children, and the factors that influence a parent's decision to use CAM for ARTI in children. This research aimed to address this knowledge gap. METHOD: This research used a qualitative descriptive approach. Parents residing in Greater Melbourne, Australia, who had children aged from 0-12 years, and had used CAM for treating ARTI in their children in the last 12 months, were eligible to participate. Parents' perspectives were captured using individual semi-structured interviews, which were then transcribed verbatim. Data were analysed using content analysis. RESULTS: Twenty-four families were interviewed. Several strategies to improve trustworthiness were implemented. Three themes underpinning the parents' decision to use CAM emerged from the data: safety, internal drivers and external drivers. Parents used a breadth of different treatments, predominantly food as medicine, followed by aromatherapy and other CAM remedies typically found in the kitchen, to manage ARTI in their children. Parents often used both CAM practitioners and mainstream medicine to manage ARTI in their children. While mainstream medicine was typically used to rule out any sinister pathology, CAM was often used as a frontline treatment option, with food as medicine (e.g. soups) dominating. This was due in part to concerns regarding the negative aspects of pharmaceutical use. Parents utilised a diverse range of information sources to inform their decision-making, including friends, families and the internet; traditional sources of research evidence were generally not used. CONCLUSION: Child safety was a major factor influencing a primary carer's decision to utilise CAM for ARTI. The safety and effectiveness of remedies utilised by parents now warrants further investigation.

Are clinical practical guidelines (CPGs) useful for health services and health workforce planning? A critique of diabetes CPGs.

AIMS: Chronic disease management is increasingly informed by clinical practice guidelines (CPGs). However, their implementation requires not only knowledge of guideline content by clinicians and practice processes that support implementation, but also a health workforce with the capacity to deliver care consistent with CPGs. This has a health services planning as well as a health workforce dimension. However, it is not known whether CPGs are described in a way that can inform health services and health workforce planning and potentially drive better quality care. This study aimed to ascertain whether CPGs are useful for health service and health workforce planning. METHODS: This question was explored taking diabetes mellitus as a case study. A systematic search of Medline, EMBASE, CINAHL and Scopus was carried out to identify all CPGs relating to the management of diabetes mellitus in the primary healthcare setting. The search was limited to guidelines published in the English language between 2003 and 2009. The quality of guidelines was assessed against a subset of criteria set by the Appraisal of Guidelines for Research and Evaluation (AGREE) collaboration. RESULTS: Seventy-five diabetes-related CPGs were identified, of which 27 met the inclusion criteria. In terms of quality, many guidelines adopted evidence-based recommendations for diabetes care (59%) and most were endorsed by national authorities (70%). With regards to coverage of 17 identified subpopulations, guidelines were generally selective in the populations they covered. Whilst many provided adequate coverage of common complications and comorbidities, approaches to management for those with reduced capacity for effective diabetes self-care were largely absent, except for indigenous populations. CONCLUSIONS: Clinical practice guidelines are potentially useful for health services and health workforce planning, but would be more valuable for this purpose if they contained more detail about care protocols and specific skills and competencies, especially for subpopulations who would be expected to have reduced capacity for effective self-care. If service planning ignores these subgroups that tend to require more resource-intensive management, underprovision of services is likely.

Clinical efficacy of horsechestnut seed extract in the treatment of venous ulceration.

OBJECTIVE: To evaluate the clinical efficacy of orally administered horsechestnut seed extract in the treatment of venous leg ulcers. METHOD: In a prospective triple-blind randomised placebo-controlled trial, 54 patients with venous leg ulcers from a large South Australian community nursing service were randomly allocated to receive horsechestnut seed extract (n=27) or placebo (n=27) for 12 weeks. Ulcers were assessed at weeks 0, 4, 8 and 12 utilising a wound assessment tool and the Alfred/Medseed Wound Imaging System. RESULTS: The difference between groups in the number of healed leg ulcers and change in wound surface area, depth, volume, pain and exudate was not statistically significant. However, horsechestnut seed extract did have a significant effect on the percentage of wound slough over time (RM-ANOVA F=2.76, p=0.045) and on the number of dressing changes at week 12 (t=-2.71, p=0.009). CONCLUSION: Even though horsechestnut seed extract is likely to attenuate the pathogenesis of venous insufficiency and, in turn, facilitate venous ulcer healing, the current study did not statistically support such a claim. However, taking into account the small sample and insufficient power of the trial, and the significant improvement in wound slough and visit frequency, it appears that it may be useful in the management of venous leg ulcers.

Making sense of the venous leg ulcer debate: a literature review.

Venous leg ulcers cause patients much distress. Treating them is expensive, with many hidden costs. As understanding of the causes and development of this condition improves, debate over the best treatments or treatment combinations is growing.

Neuroprotective actions in vivo and electrophysiological actions in vitro of 202W92.

202W92 (R-(-)-2,4-diamino-6-(fluromethyl)-5-(2,3,5-trichlorophenyl)pyrimidine) is a novel compound in the same chemical series as the antiepileptic drug lamotrigine and the neuroprotective sipatrigine. Here 202W92 was quantitatively assessed as a neuroprotective agent in focal cerebral ischaemia, and as an inhibitor of sodium and calcium channels and of synaptic transmission. In the rat permanent middle cerebral artery occlusion (MCAO) model of acute focal ischaemia, 202W92 reduced infarct volume by 75% in cortex and by 80% in basal ganglia, with ED(50) approximately 2 mg/kg (single i.v. dose, 10 min post-occlusion). In whole-cell current recordings from single cells, 202W92 completely and reversibly inhibited voltage gated sodium channels (IC(50) 3 x 10(-6) M) in rat freshly-isolated cortical neurons and in the GH(3) pituitary cell line. 202W92 also inhibited a nifedipine-sensitive fraction (approximately 35%) of native high-voltage-activated (HVA) calcium current in rat cortical neurons (IC(50) 15 x 10(-6) M) and weakly inhibited low-voltage-activated (LVA) calcium currents of the recombinant alpha1I-mediated T-type (IC(50)>100 x 10(-6) M). The drug inhibited the amplitude and frequency of 4-aminopyridine-evoked glutamatergic excitatory post-synaptic currents (EPSCs). In conclusion, 202W92 is an effective neuroprotective agent when administered post-ischaemia and a potent sodium channel inhibitor in vitro.

Electrophysiology of sipatrigine: a lamotrigine derivative exhibiting neuroprotective effects.

Sipatrigine (BW619C89), a derivative of the antiepileptic agent lamotrigine, has potent neuroprotective properties in animal models of cerebral ischemia and head injury. In the present study we investigated the electrophysiological effects of sipatrigine utilizing intracellular current-clamp recordings obtained from striatal spiny neurons in rat corticostriatal slices and whole-cell patch-clamp recordings in isolated striatal neurons. The number of action potentials produced in response to a depolarizing current pulse in the recorded neurons was reduced by sipatrigine (EC(50) 4.5 microM). Although this drug preferentially blocked action potentials in the last part of the depolarizing current pulse, it also decreased the frequency of the first action potentials. Sipatrigine also inhibited tetrodotoxin-sensitive sodium (Na(+)) current recorded from isolated striatal neurons. The EC(50) for this inhibitory action was 7 microM at the holding potential (V(h)) of -65 mV, but 16 microM at V(h) = -105, suggesting a dependence of this pharmacological effect on the membrane potential. Moreover, although the inhibitory action of sipatrigine on Na(+) currents was maximal during high-frequency activation (20 Hz), it could also be detected at low frequencies. The amplitude of excitatory postsynaptic potentials (EPSPs), recorded following stimulation of the corticostriatal pathway, was depressed by sipatrigine (EC(50) 2 microM). This inhibitory action, however, was incomplete; in fact maximal concentrations of this drug reduced EPSP amplitude by only 45%. Sipatrigine produced no increase in paired-pulse facilitation, suggesting that the modulation of a postsynaptic site was the main pharmacological effect of this agent. The inhibition of voltage-dependent Na(+) channels exerted by sipatrigine might account for its depressant effects on both repetitive firing discharge and corticostriatal excitatory transmission. The modulation of Na(+) channels described here, as well as the previously observed inhibition of high-voltage-activated calcium currents, might contribute to the neuroprotective efficacy exerted by this compound in experimental models of in vitro and in vivo ischemia.

Automated exchange transfusion for life-threatening plasmodium falciparum malaria--lessons relating to prophylaxis and treatment.

We report a case of traveller to Kenya who contracted severe plasmodium falciparum malaria complicated by disseminated intravascular coagulation and acute renal failure. She had taken no antimalarial prophylaxis in view of concerns in the media regarding the adverse effects of mefloquine. There was a protracted delay before the diagnosis of malaria was made. Clinical recovery occurred following treatment with intravenous quinine, haemofiltration and manual/automated red-cell exchange transfusions. Automated red-cell exchange transfusion resulted in a marked decrease in the parasitaemia, before a response to quinine therapy would have been anticipated, leading to a successful outcome thereafter. In conjunction with other groups we therefore feel that exchange transfusions should be considered in seriously ill patients with falciparum malaria, multiorgan complications and parasitaemias greater than 10%.

Long-term beneficial effects of BW619C89 on neurological deficit, cognitive deficit and brain damage after middle cerebral artery occlusion in the rat.

4-Amino-2-(4-methyl-1-piperazinyl)-5-(2,3,5-trichlorophenyl)pyrimidine (BW619C89) is a sodium channel antagonist which when administered parenterally reduces neurological deficit and infarct volume after middle cerebral artery occlusion in rats. We have investigated whether BW619C89 administered orally before middle cerebral artery occlusion is cerebroprotective when rats are assessed at one day after stroke, and whether cerebroprotection is long lasting and related to functional recovery. A cerebroprotective oral dose of BW619C89 (20 mg/kg) was used to determine whether reduction in infarct volume is long lasting and can be enhanced with continued therapy, and whether behavioural deficits occurring after middle cerebral artery occlusion such as disturbances in cognition and motor coordination are ameliorated by treatment with BW619C89. Rats received sham surgery or middle cerebral artery occlusion with a single treatment of BW619C89 (20 mg/kg) 1 h before middle cerebral artery occlusion, a double treatment group receiving 20 mg/kg BW619C89 1 h before and 10 mg/kg 5 h after middle cerebral artery occlusion, or continued treatment with BW619C89 for up to five days. Neurological deficit, assessed from days 1 to 21, and at 70 days after middle cerebral artery occlusion, was reduced to a similar extent in all three groups of rats treated with BW619C89, compared with vehicle-treated controls. At 70 days after middle cerebral artery occlusion, all groups performed at control level. Vehicle-treated rats were impaired in the Morris water maze and step-through passive avoidance paradigm five to eight weeks after middle cerebral artery occlusion, when neurological deficit was minimal. These deficits were partially alleviated, to a similar extent, by all of the three treatments with BW619C89. Total volumes of brain damage, assessed at 70 days after middle cerebral artery occlusion in Luxol Fast Blue- and Cresyl Violet-stained coronal sections, were reduced in all three groups of BW619C89-treated rats, to 46% in the single, 50% in the double and 58% in the continued treatment group, compared with vehicle-treated rats. Extent of brain damage correlated with extent of impairment of the rats in the water maze. These findings suggest that BW619C89 has long-lasting cerebroprotective effects with advantageous functional consequences after single oral administration in a rodent model of stroke. Prolonged treatment with BW619C89 did not significantly enhance the cerebroprotective effects. Deficits in performance of rats in the water maze and step-through passive avoidance tasks indicate sustained cognitive impairment after middle cerebral artery occlusion. The reductions in brain damage by BW619C89 correlated with significant long-term functional improvement.

Inhibition of human N-type voltage-gated Ca2+ channels by the neuroprotective agent BW619C89.

Human N-type Ca2+ channels were rapidly and reversibly inhibited by 5-100 microM BW619C89 (IC50 = 16.4 microM at Vtest = + 10 mV and Vhold = - 90 mV). In the presence of 20 microM BW619C89, activation kinetics were significantly faster. The degree of inhibition observed was affected by both test and holding potential, indicating state-dependent interactions with the N-type Ca2+ channel.

Vicious cycle involving Na+ channels, glutamate release, and NMDA receptors mediates delayed neurodegeneration through nitric oxide formation.

The mechanisms by which neurons die after cerebral ischemia and related conditions in vivo are unclear, but they are thought to involve voltage-dependent Na+ channels, glutamate receptors, and nitric oxide (NO) formation because selective inhibition of each provides neuroprotection. It is not known precisely what their roles are, nor whether they interact within a single cascade or in parallel pathways. These questions were investigated using an in vitro primary cell culture model in which striatal neurons undergo a gradual and delayed neurodegeneration after a brief (5 min) challenge with the glutamate receptor agonist NMDA. Unexpectedly, NO was generated continuously by the cultures for up to 16 hr after the NMDA exposure. Neuronal death followed the same general time course except that its start was delayed by approximately 4 hr. Application of the NO synthase inhibitor nitroarginine after, but not during, the NMDA exposure inhibited NO formation and protected against delayed neuronal death. Blockade of NMDA receptors or of voltage-sensitive Na+ channels [with tetrodotoxin (TTX)] during the postexposure period also inhibited both NO formation and cell death. The NMDA exposure resulted in a selective accumulation of glutamate in the culture medium during the period preceding cell death. This glutamate release could be inhibited by NMDA antagonism or by TTX, but not by nitroarginine. These data suggest that Na+ channels, glutamate receptors, and NO operate interdependently and sequentially to cause neurodegeneration. At the core of the mechanism is a vicious cycle in which NMDA receptor stimulation causes activation of TTX-sensitive Na+ channels, leading to glutamate release and further NMDA receptor stimulation. The output of the cycle is an enduring production of NO from neuronal sources, and this is responsible for delayed neuronal death. The same neurons, however, could be induced to undergo more rapid NMDA receptor-dependent death that required neither TTX-sensitive Na+ channels nor NO.

Neuroprotective effects of a use-dependent blocker of voltage-dependent sodium channels, BW619C89, in rat middle cerebral artery occlusion.

BW619C89 [4-amino-2-(4-methyl-1-piperazinyl)-5-(2,3,5- trichlorophenyl)pyrimidine is a use-dependent blocker of voltage-dependent sodium channels that blocks veratrine-induced glutamate release in vitro. The aim of this study is to determine if BW619C89 inhibits glutamate release and is neuroprotective in cerebral ischemia produced by proximal middle cerebral artery (MCA) occlusion in rats. Infarct volume was determined at 24 hr after permanent MCA occlusion from 2,3,5-triphenyltetrazolim hydrochloride-stained sections. Pretreatment with BW619C89 (10, 20, 30 and 50 mg/kg i.v. of mesylate salt) decreased infarct volume in a dose-dependent fashion maximal at 30 mg/kg compared to saline controls. Treatment with 30 mg/kg up to 45 min after MCA occlusion also was effective. Microdialysate glutamate in rats treated with 30 mg/kg of drug before MCA occlusion was decreased in both caudate (ischemic core) and rostral cortex (penumbra) compared to controls. BW619C89 did not induce significant arterial hypotension, except when it was administered by rapid bolus administration. In this case, the hypotension was transient and did not reduce efficacy or superficial cortical blood flow. BW619C89 did not induce the 72 kD heat shock protein in cingulate gyrus or retrosplenial cortex as did MK801, suggesting that BW619C89 does not injure neurons in these regions as do N-methyl-D-aspartate antagonists. These results suggest that inhibition of glutamate release by BW619C89 may be an effective and nontoxic treatment for stroke.

BW619C89, a glutamate release inhibitor, protects against focal cerebral ischemic damage.

BACKGROUND AND PURPOSE: The excitatory amino acid neurotransmitter glutamate is involved in excitotoxic brain injury and neurodegeneration after cerebral ischemia. Therefore, compounds that block the release of glutamate may be useful as cerebroprotective agents. The purpose of this study was to evaluate the cerebroprotective properties of a glutamate release inhibitor, BW619C89. METHODS: In the studies reported here, the effect of BW619C89 [4-amino-2-(4-methyl-1-piperazinyl)-5-(2,3,5-trichlorophenyl)pyrimidine] on neurotransmitter release (endogenous amino acids, gamma-aminobutyric acid, and acetylcholine) from slices of rat brain cerebral cortex in vitro has been determined. The neuroprotective efficacy of BW619C89 has been evaluated using the middle cerebral artery occlusion model of focal cerebral ischemia in the Fischer 344 rat. RESULTS: In the in vitro studies, BW619C89 inhibited veratrine- (but not potassium-) evoked release of both endogenous glutamate and aspartate from rat cerebral cortex slices with IC50 values of approximately 5 microM. BW619C89 was approximately 10-fold less potent to inhibit veratrine-evoked 3H-gamma-aminobutyric acid release (IC50 = 51 microM), fourfold less potent to inhibit 3H-acetylcholine release (IC50 = 21 microM), and at 10 microM had only weak activity at excitatory amino acid (N-methyl-D-aspartate, kainate, and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) binding sites. When administered intravenously to Fischer 344 rats 5 minutes after permanent middle cerebral artery occlusion, BW619C89 produced marked reductions of both total (cortex and basal ganglia) and cortical infarct volumes. Cortical infarct size was reduced by 20% at a dose of BW619C89 of 5 mg/kg (n = 6, not significant); 43% at 10 mg/kg (n = 8, P < .01); 59% at 20 mg/kg (n = 8, P < .001); 61% at 30 mg/kg (n = 8, P < .001), and 53% at 40 mg/kg (n = 8, P < .001). BW619C89 at doses of 20 and 30 mg/kg also significantly reduced noncortical (basal ganglia) infarct volumes, demonstrating that a proportion of this tissue also appears to be salvageable. Behavioral effects observed were dose related, generally minor, and at doses of 20 mg/kg IV and above consisted of body tremor and mild ataxia lasting approximately 2 hours. CONCLUSIONS: These results suggest that glutamate release inhibitors such as BW619C89 may provide an alternative to excitatory amino acid receptor antagonists in the treatment of focal cerebral ischemia and stroke.

Studies on the mechanism of action of the novel anticonvulsant lamotrigine (Lamictal) using primary neurological cultures from rat cortex.

Whole cell and perforated patch clamp experiments were conducted on cultured cortical rat neurones (7-21 days in vitro) in order to determine the effects of the anticonvulsant and glutamate release inhibitor Lamotrigine (10-100 microM), on CNS receptors and ion channels. The compound inhibited, indiscriminately, both excitatory and inhibitory synaptic events which occurred spontaneously in cultured neural circuits. The drug did not mimic diazepam as a positive modulator of GABAA currents. In the presence of tetrodotoxin, voltage-gated potassium currents and composite currents evoked by L-glutamate were not significantly modulated even at the highest dose. Unitary, fast, presumptive-sodium spikes, evoked at low frequencies, were not blocked significantly by lamotrigine. In contrast, burst firing induced by pulsed application of L-glutamate or potassium ions was markedly depressed at 10 microM. Presumptive calcium currents were inhibited by lamotrigine at 100 microM. It is proposed that the drug inhibits epileptiform burst firing preferentially by state/activity dependent interactions with voltage gated cation channels. Potential mechanisms for inhibition of glutamate release are discussed.

Reduction of glutamate release and protection against ischemic brain damage by BW 1003C87.

BW 1003C87, 5-(2,3,5-trichlorophenyl)-2,4-diaminopyrimidine ethane sulphonic acid, has been tested for its in vitro and in vivo effects on glutamate release in rat brain tissue, and for its cerebro-protective action in two rodent models of cerebral ischemia. In rat brain slices the release of glutamate evoked by veratrine is inhibited by BW 1003C87 (IC50 = 1.6 microM). In anaesthetised rats with microdialysis probes implanted in the dorsal hippocampus the increase in extracellular glutamate evoked by veratrine is markedly reduced by co-infusion of BW 1003C87, 100 microM. In anaesthetised rats with microdialysis probes implanted in the cortex and the caudate nucleus ipsilateral to a middle cerebral artery (MCA) occlusion the increase in dialysate glutamate concentration seen in the first 2 h following MCA occlusion is markedly attenuated by the prior administration of BW 1003C87, 20 mg/kg i.v. In rats subjected to 10 min of bilateral common carotid artery occlusion the loss of CA1 pyramidal neurons (assessed 7 days later) is reduced by administration of BW 1003C87 (20 mg/kg i.v., at the time of ischemia and 4 h later). The volume of cortex showing infarction 72 h after unilateral MCA occlusion is reduced by treatment with BW 1003C87 (20 mg/kg, i.v., beginning 5 min after occlusion). Inhibition of glutamate release may provide a therapeutic approach in cerebral ischemia as well as in epilepsy.

Neurochemical and behavioral aspects of lamotrigine.

Lamotrigine (LTG), a new anticonvulsant, chemically unrelated to current antiepileptic drugs (AEDs), resembles phenytoin (PHT) and carbamazepine (CBZ) in ability to block hindlimb extension in both the maximal electroshock test and leptazol-induced seizures. Results indicate that LTG may be of value in both partial and generalized seizures. In in vitro studies, LTG has been shown to inhibit veratrine-evoked release of glutamate when a threshold depolarizing concentration (4 micrograms/ml) is used, and also inhibits aspartate release when a larger stimulus is given (10 micrograms/ml). However, LTG does not block potassium-evoked transmitter release. LTG is a less potent inhibitor of the release of gamma-aminobutyric acid (GABA), acetylcholine, noradrenaline, and dopamine. LTG blocks the neurotoxicity of kainic acid in vivo, supporting the in vitro findings, and suggests that the anticonvulsant effect of LTG may be due to inhibition of glutamate release. In a test of working memory and phencyclidine (PCP) discrimination studies, LTG had no effect, indicating no sharing of the same PCP-like side effects associated with NMDA receptor blockade. In the gerbil model of global ischemia, high doses of LTG provided protection against damage to the CA1 region of the hippocampus. Analogues of LTG of higher potency to block the release of glutamate may be necessary to ensure protection against ischemic brain damage.

Hippocampal NMDA/phencyclidine receptor binding sites are reduced following forebrain ischaemia in the gerbil.

The binding of [3H]N-(1-[2-thienyl]cyclohexyl)piperidine (TCP) to N-methyl-D-aspartate (NMDA) receptor sites in synaptic membranes prepared from the dorsal hippocampus of the ischaemic gerbil, has been studied. Forebrain ischaemia was induced by 10 min bilateral carotid occlusion and receptor binding determined in the dorsal hippocampus 1 week later. [3H]TCP binding capacity was significantly reduced by 28% in ischaemic tissue with no change in affinity. This result is consistent with the involvement of NMDA receptors in ischaemic brain damage.

Effect of cortical kindling on [3H]D-aspartate uptake and glutamate metabolism in rats.

The effects of cortical kindling in rats on [3H]D-aspartate uptake and on glutaminase and glutamine synthetase activities has been studied. The high affinity uptake of [3H]D-aspartate in control cortical tissue (Km approximately 2 microM) was undetectable in the kindled tissue, whilst the enzyme activities were unchanged. A loss of the high-affinity uptake sites for excitatory amino acids may be a contributing factor to the kindling phenomenon.