Occurrence of bisphosphonate-associated osteonecrosis of the jaws in individuals with rheumatoid arthritis - a systematic review.

BACKGROUND: To access the occurrence of bisphosphonate-associated osteonecrosis of the jaw (BAONJ) in individuals with rheumatoid arthritis (RA). MATERIAL AND METHODS: Observational studies that evaluated the occurrence of BAONJ in individuals with RA (BAONJ-RA) were considered for inclusion. Electronic searches were performed up to December 2022 in six databases and in the grey literature. The study selection, data extraction, and quality assessment of the included studies according to the Joanna Briggs Institute Critical Appraisal Checklists was performed. The certainty of evidence was evaluated using the GRADE approach. RESULTS: Five studies were included three cohort and two cross-sectional. The sample size of subjects with RA ranged from 16 to 3201. Together, the studies presented 36 cases of BAONJ-RA. Prevalence of BAONJ-RA ranged from 0.094% to 56.25%. The incidence ranged from 0.4% to 2.21. Women between the 6th and 8th decade of life were the most affected. Alendronate (n=5) and zoledronic acid (n=9), orally and intravenously, respectively, were the most used bisphosphonates. The duration of bisphosphonates use ranged from 2.7 to 8 years. The certainty of evidence was very low. CONCLUSIONS: The occurrence of BAONJ-RA is low. However, the certainty of the evidence was very low for this outcome.

Worldwide trends on molar incisor and deciduous molar hypomineralisation research: a bibliometric analysis over a 19-year period.

AIM: To identify the worldwide trends in scientific evidence and gaps in knowledge regarding molar incisor hypomineralisation (MIH) and deciduous molar hypomineralisation/hypomineralised second primary molars (DMH/HSPM), exploring the contribution of authors and countries, possible etiological factors and proposed treatments, in order to guide future research in the area. METHODS: Searches were conducted in MEDLINE, Scopus, Web of Science, Cochrane Library, Lilacs/BBO, Embase and Google Scholar. Studies employing the terms MIH, DMH/HSPM and their linguistic variations were included. The following data were extracted: title, authors, year and journal of publication and first author's affiliation country. Studies were categorized according to topic, dentition, study design, etiological factors and types of treatments. Categories were analysed in relation to their distribution, co-occurrence, cross-correlation and/or autocorrelation. RESULTS: Five hundred and three studies were included. The most published authors were Manton D (n = 47), de Souza JF (n = 22) and Ghanim A (n = 22) and four main collaboration clusters have been identified. Most of the studies were conducted on permanent dentition (MIH) (87.4%); with observational design (57.2%). The "European Archives of Paediatric Dentistry" was the most published journal (13.3%) and a significant increase in the number of publications was observed in the last decade. MIH was most studied in relation to prevalence/incidence, systemic factors involved in its aetiology and treatment with composite restorations, while a gap in knowledge was observed for extraction and sealants. Less studies were published on DMH/HSPM and most of them evaluated risk factors or prevalence/incidence. The gap of knowledge was observed in relation to treatments and patient's quality of life. CONCLUSIONS: This bibliometric review provided a comprehensive overview of research in MIH and DMH/HSPM over the past 19 years. Within the limitations of the present study, the following conclusions can be drawn: global trends point to an increasing peak of scientific publication, especially in the last decade, while there is a shortage of clinical studies on treatments, mainly evaluating tooth extractions. Finally the multifactorial nature should be further explored, considering environmental and systemic factors together.

MTT versus other cell viability assays to evaluate the biocompatibility of root canal filling materials: a systematic review.

OBJECTIVES: This systematic review aimed to compare the cytotoxicity of root canal filling materials (RCFMs) assessed using tetrazolium salt-based tests (TSBT), including the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, with those obtained using other cell viability assays. METHODS: A search was performed on PubMed, Scopus, Web of Science and OpenGrey up to March 2019, followed by a manual search. According to the Participants, Exposure, Comparator and Outcomes (PECO) criteria, in vitro studies that evaluated the cytotoxic effect of RCFMss on animal and/or human cells through TSBT and at least one other viability assay were compared. The methodological quality of selected papers was assessed using ToxRTool® and SciRAP® . Data were analysed using Wilcoxon's signed-rank test for paired samples and linear weighting kappa. RESULTS: A total of 230 non-duplicated records were identified. After applying the eligibility criteria, 55 studies were selected for methodological evaluation, seven were selected by manual searching, 22 were excluded for methodological reasons, and 40 were included. A total of 410 comparisons were performed between TSBT and distinct cell viability tests (DCVT). MTT had moderate concordance with DCVT using human cells (n = 138 samples) (P = 0.507; k = 0.4225) and animal cells (n = 122 samples) (P = 0.124; k = 0.5775). XTT had good concordance using human (n = 110 samples) (P = 0.507; k = 0.6336) and animal cells (n = 12 samples) (P = 0.564; k = 0.6604). MTT, XTT, WST and MTS assays showed moderate concordance with DCVT (n = 410 samples) (P = 0.375; k = 0.5138) and complete agreement in 226 samples. DISCUSSION: The included studies had methodological heterogeneity that was minimized by the systematic review methodology. CONCLUSIONS: MTT and XTT do not cause over- or underestimation of cell viability during cytotoxicity screening of root canal filling materials, implying that these assays can be considered reliable for this purpose. Nonetheless, the development of protocols for the cytotoxic screening of these materials on 3D tissue-like cultures aiming to improve their predictability in the clinical scenario is suggested.

[Acyclovir-induced acute renal failure: An under-estimated secondary effect?]. / Insuficiencia renal aguda por aciclovir, un efecto secundario infraestimado?

The increasing use of oral or IV acyclovir to treat infections caused by herpesviridae family involves a rise in the number of observed adverse effects. Neuro- and nephrotoxicity are most serious observed and reported secondary effects. The monitoring of renal function is essential to detect these cases since it develops as a non-oliguric renal failure. Because of this, the outpatient and oral use of the drug can result in an underestimation of the number of cases reported. We report two patients with genital herpes and viral encephalitis that required IV acyclovir. Both inpatients developed an acute renal failure that resolved after the drug was withdrawn.

Insuficiencia renal aguda por aciclovir, ¿un efecto secundario infraestimado? / Acyclovir-induced acute renal failure: an under-estimated secondary effect?

En la actualidad, el mayor uso de aciclovir, por vía intravenosa u oral, para tratar infecciones de la familia Herpesviridae, conlleva un aumento del número de efectos adversos descritos. La neurotoxicidad y nefrotoxicidad son los efectos secundarios más graves que se han comunicado. La monitorización de la función renal es fundamental para detectar estos casos, pues cursa como insuficiencia renal no oligúrica. Por ello, el uso ambulatorio y oral del fármaco puede dar lugar a una infraestimación del número de casos totales. Presentamos los casos de 2 pacientes que por su patología de base (herpes genital y encefalitis viral) precisaron aciclovir intravenoso, y que durante su estancia hospitalaria desarrollaron insuficiencia renal aguda no oligúrica, que cedió al suspender la administración del fármaco

The increasing use of oral or IV acyclovir to treat infections caused by herpesviridae family involves a rise in the number of observed adverse effects. Neuro- and nephrotoxicity are most serious observed and reported secondary effects. The monitoring of renal function is essential to detect these cases since it develops as a non-oliguric renal failure. Because of this, the outpatient and oral use of the drug can result in an underestimation of the number of cases reported. We report two patients with genital herpes and viral encephalitis that required IV acyclovir. Both inpatients developed an acute renal failure that resolved after the drug was withdrawn

Efecto de una intervención farmacéutica en los parámetros clínicos de pacientes con síndrome metabólico: estudio piloto prospectivo «antes-después» / Effect of a pharmacist intervention on clinical parameters in metabolic syndrome patients: a prospective open-label pilot study

Objetivo: Evaluar la funcionalidad del seguimiento farmacoterapéutico en pacientes con síndrome metabólico como herramienta que permite identificar y resolver situaciones de descontrol de los factores de riesgo cardiovascular, o bien situaciones en las que la intervención farmacoterapéutica no se realiza con la intensidad debida según la situación clínica del paciente. Diseño: Estudio piloto prospectivo «antes-después». Emplazamiento: Centro de Salud Torcal de Antequera (Málaga). Participantes: Pacientes con síndrome metabólico de un cupo médico. Intervención: Se llevaron a cabo intervenciones farmacéuticas centradas, fundamentalmente, en acordar con el médico modificaciones en la farmacoterapia del paciente. Mediciones principales (método): Hemoglobina glucosilada (cromatografía de alta resolución), colesterol unido a lipoproteínas de alta densidad (homogéneo directo) y baja densidad (fórmula Friedewald), colesterol total (adaptación del enzimático de Stadtman), triglicéridos (enzimático lipasa/glicerolcinasa), índice de masa corporal, presión arterial, glucemia basal en sangre venosa (enzimático hexocinasa) y uso de ácido acetilsalicílico. Resultados: El número de pacientes que comenzaron a utilizar ácido acetilsalicílico aumentó de forma significativa. No hubo variaciones significativas del resto de los parámetros, ni del número de pacientes que alcanzaban los objetivos terapéuticos. Conclusiones: Detectar resultados negativos asociados a la medicación permite identificar situaciones de descontrol de los factores de riesgo cardiovascular y otras en las que la intervención farmacoterapéutica no se realiza con la intensidad debida según la situación clínica del paciente. La intervención farmacéutica aumentó de forma significativa el número de pacientes que requerían tomar ácido acetilsalicílico (AU)

Objectives: To evaluate the functionality of pharmacotherapy follow-up in patients with metabolic syndrome (MS) as a tool to identify and resolve situations in which there is lack of control of cardiovascular risk factors, as well as other situations in which the pharmacist intervention lacks the intensity necessary to successfully address the patient’s clinical condition. Design: Prospective pretest-posttest pilot study. Setting: Centro Salud Torcal de Antequera, Málaga, Spain. Participants: Patients with MS treated by the same physician. Intervention: Interventions were carried out focusing basically on modifying patient pharmacotherapy by mutual agreement with the physician. Main measurements (Method): Glycated hemoglobin (high-resolution gas chromatography), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels (Friedewald formula), total cholesterol level (adaptation of the Stadtman enzymatic method), triglycerides (enzymatic method using lipase/glycerol kinase), body mass index, arterial pressure, basal blood glucose (enzymatic method using hexokinase) and the use of acetylsalicylic acid (ASA). Results: The number of patients who began using acetyl ASA increased significantly. There were no significant changes in the remaining parameters or in the number of patients who achieved the therapeutic objectives. Conclusions: The detection of negative clinical outcomes of drug therapy makes it possible to identify those situations in which there is lack of control of cardiovascular risk factors, as well as other situations in which the pharmacist intervention lacks the intensity necessary to successfully address the patient’s clinical condition. The pharmacist intervention significantly increased the number of patients who required the use of ASA (AU)

The cannabinoid receptor agonist WIN 55,212-2 attenuates the effects induced by quinolinic acid in the rat striatum.

The ability of CB(1) receptors to regulate the release of glutamate in the striatum, together with the finding that, in experimental models of Huntington disease (HD), both endocannabinoid levels and CB(1) receptor densities are reduced, has prompted the investigation on the neuroprotective role of the cannabinoids in HD. Quinolinic acid (QA) is an excitotoxin that, when injected in the rat striatum reproduces many features of HD and that acts by stimulating glutamate outflow. The aim of the present study was to test the ability of the cannabinoid receptor agonist WIN 55,212-2 to prevent the effects induced by QA in the rat striatum. In microdialysis experiments, probe perfusion with WIN 55,212-2 significantly and dose-dependently prevented the increase in extracellular glutamate induced by QA. In electrophysiological recordings in corticostriatal slices, the application of WIN 55,212-2 prevented QA-induced reduction of the field potential amplitude. Both effects of WIN 55,212-2 were prevented by the CB(1) receptor antagonist AM 251. In in vivo experiments, intrastriatal WIN 55,212-2 significantly attenuated the striatal damage induced by QA, although no significant effects were observed on a behavioural ground. These data demonstrate that the stimulation of CB(1) receptors might lead to neuroprotective effects against excitotoxic striatal toxicity.

Adenosine A 2A receptor antagonists prevent the increase in striatal glutamate levels induced by glutamate uptake inhibitors.

Active uptake by neurons and glial cells is the main mechanism for maintaining extracellular glutamate at low, non-toxic concentrations. Activation of adenosine A(2A) receptors increases extracellular glutamate levels, while A(2A) receptor antagonists reduce stimulated glutamate outflow. Whether a modulation of the glutamate uptake system is involved in the effects elicited by A(2A) receptor blockers has never been investigated. This study examined the ability of adenosine A(2A) receptor antagonists to prevent the increase in glutamate levels induced by blockade of the glutamate uptake. In rats implanted with a microdialysis probe in the dorsal striatum, perfusion with 4 mm l-trans-pyrrolidine-2,4-dicarboxylic acid (PDC, a transportable competitive inhibitor of glutamate uptake), or 10 mm dihydrokainic acid (DHK, a non-transportable competitive inhibitor that mainly blocks the glial glutamate transporter GLT-1), significantly increased extracellular glutamate levels. The effects of PDC and DHK were completely prevented by the adenosine A(2A) receptor antagonists SCH 58261 (0.01 mg/kg i.p.) and/or ZM 241385 (5 nm via probe). Since an impairment in glutamate transporter function is thought to play a major role in neurodegenerative disorders, the regulation of glutamate uptake may be one of the mechanisms of the neuroprotective effects of A(2A) receptor antagonists.

Modulation of glutamate release and excitotoxicity by adenosine A2A receptors.

Because an increased glutamate outflow is thought to play a crucial role in triggering excitotoxic neuronal death, drugs able to regulate glutamate release could be effective for the management of neurodegenerative diseases. In this article, the authors discuss the hypothesis that adenosine A2A receptor antagonists (A2A antagonists) may belong to the aforementioned category. In rats bilaterally lesioned with the excitotoxin quinolinic acid (QA) in the striatum, the A2A antagonist SCH 58261 significantly reduced the motor, EEG, and neuropathologic changes induced by the lesion. Such effects of SCH 58261 occurred only at low doses and were paralleled by an inhibition of QA-stimulated glutamate release. The role played by A2A antagonists in the regulation of glutamate outflow was also confirmed by preliminary results obtained in the model of paired-pulse stimulation in corticostriatal slices. Conversely, based on data obtained in cultured striatal neurons, A2A antagonists appear unable to directly inhibit NMDA effects. In conclusion, A2A antagonists show clear neuroprotective effects in models of brain injury, although their actual therapeutic potential needs to be confirmed in a wider range of doses and in models of neurodegenerative diseases in which presynaptic and postsynaptic effects play different relative roles.

Uso profiláctico y terapéutico del ibuprofeno en el cierre del ductus en el recién nacido pretérmino / Prophylactic and therapeutic use of ibuprofen in ductus closure in the preterm newborn

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The selective mGlu(5) receptor agonist CHPG inhibits quinpirole-induced turning in 6-hydroxydopamine-lesioned rats and modulates the binding characteristics of dopamine D(2) receptors in the rat striatum: interactions with adenosine A(2a) receptors.

In 6-hydroxydopamine-lesioned rats, the selective mGlu(5) receptor agonist (RS)-2-Cholro-5-Hydroxyphenylglycine (CHPG, 1-6 microg/10 microl intracerebroventricularly) significantly inhibited contralateral turning induced by quinpirole and, to a lesser extent, that induced by SKF 38393. The inhibitory effects of CHPG on quinpirole-induced turning were significantly potentiated by an adenosine A(2A) receptor agonist (CGS 21680, 0.2 mg/kg IP) and attenuated by an A(2A) receptor antagonist (SCH 58261, 1 mg/kg IP). In rat striatal membranes, CHPG (100-1,000 nM) significantly reduced the affinity of the high-affinity state of D(2) receptors for the agonist, an effect potentiated by CGS 21680 (30 nM). These results show the occurrence of functional interactions among mGlu(5), adenosine A(2A), and dopamine D(2) receptors in the regulation of striatal functioning, and suggest that mGlu(5) receptors may be regarded as alternative/integrative targets for the development of therapeutic strategies in the treatment of Parkinson's disease.

SCH 58261 (an adenosine A(2A) receptor antagonist) reduces, only at low doses, K(+)-evoked glutamate release in the striatum.

The aim of the present work was to determine whether systemic administration of the adenosine A(2A) receptor antagonist, SCH 58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4,triazolo[1,5-c]pyrimidine), could modulate striatal glutamate outflow in the rat. Microdialysis experiments were performed in male Wistar rats implanted with microdialysis probes in the striatum. Pretreatment (15 min before) with SCH 58261 (0.01 and 0.1, but not 1 mg/kg intraperitoneally) significantly prevented K(+)-stimulated glutamate release. These results suggest that SCH 58261 could possess neuroprotective effects in the low dose range, while, at higher doses, the occurrence of additional mechanisms may limit the neuroprotective potential of this drug.

The mGlu5 receptor agonist CHPG stimulates striatal glutamate release: possible involvement of A2A receptors.

The intrastriatal perfusion of the selective metabotropic glutamate (mGlu)5 receptor agonist (RS)-2-chloro-5-hydroxy-phenylglycine (CHPG, 1000 microM) significantly increased (approximately + 100%, p < 0.05) glutamate extracellular levels with respect to basal values. The potentiating effect of CHPG was prevented by the selective mGlu5 receptor antagonist 2-methyl-6(phenyl-ethynyl)-pyridine (MPEP, 250 microM)) and by the adenosine A2A receptor antagonist SCH 58261 (2 mg/kg, i.p.). The results show that mGlu5 receptors are involved in the regulation of striatal glutamate release and suggest an involvement of adenosine A2A receptors in mGlu5 receptor-mediated effects.

Age-related decline in the functional response of striatal group I mGlu receptors.

In order to verify whether striatal group I metabotropic glutamate (mGlu) receptors undergo functional alteration in ageing, the effects induced by the selective agonist 3,5-dihydroxyphenylglycine (DHPG) in the striatum of young (3 months) and aged (24-25 months old) rats were compared. The ability of DHPG to stimulate phosphoinositide (PI) hydrolysis (striatal slices), to influence striatal dopamine release (in vivo microdialysis) and to potentiate the effects of NMDA on extracellular field potential amplitude (extracellular recordings on striatal slices) was reduced in the striatum of old vs young rats. These results show an age-dependent reduction in the functional response of striatal group I mGlu receptors, which may be one of the factors underlying the reduced ability aged striatum to integrate information.

Metabotropic glutamate receptor agonist (1S,3R-ACPD) increased frontal cortex dopamine release in aged but not in young rats.

The effects of the metabotropic glutamate (mGlu) receptor agonist (1S,3R)-1-Amino cyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) infusion on frontal cortex dopamine extracellular levels were studied by microdialysis in young (3 months) and aged (24 months) rats. Basal dopamine levels were significantly higher in young than in aged rats. (1S,3R)-ACPD (1 mM) significantly increased dopamine efflux in aged rats, an effect which was antagonized by the mGlu receptor antagonist, (S)-alpha-methyl-4-carboxypheniylglycine (MCPG) (2 mM). On the contrary, (IS,3R)-ACPD up to the concentration of 2 mM failed to influence dopamine extracellular levels in young rats. These results suggest that the agonist of mGlu receptor group I and/or II can improve dopamine release under conditions of deficiency of extracellular dopamine concentration as observed in aging.

Influences of hypothyroidism on lipid composition and inositol lipid-linked receptors responsiveness and protein kinase C (PKC) activity in the cerebral cortex of Lewis rats.

The influence of hypothyroidism (HO) induced by treatment with propylthiouracil on lipid composition, receptor responsiveness of M1-muscarinic receptors (M1AChRs) and metabotropic glutamate receptors (mGluRs) as well as on protein kinase C (PKC) activity was investigated in the cerebral cortex of Lewis rats. HO did not influence the lipid composition. There was a significant 2-fold increase of efficacy and 6-fold decrease of potency of carbachol-induced inositol phosphate (IP) accumulation in HO, with respect to control rats. The efficacy of trans-(1S,3R)-1-amino-1,3-cyclopentanedicarboxylic acid (ACPD)-induced IP accumulation was also higher in HO (by 50%), without differences in EC50 values. The activities of soluble calcium-dependent and calcium-independent PKC were higher in HO than in control rats (both roughly 30%); membrane-associated PKCs were not modified. The data indicate that HO induces an increased responsiveness of M1AChRs and mGluRs and a rise in the soluble PKC activity that could be available and ready for translocation.

Carbachol-induced accumulation of inositol phosphates and its modulation by excitatory amino acids in cortical slices of young and aged rats with down-regulation of muscarinic M-1 receptors.

The effects of a subacute intoxication with diisopropyl fluorophosphate (DPF) on total muscarinic acetylcholine receptor sites (mAChRs) and M-1 AChRs were evaluated in the cerebral cortex of young (2-4 months) and aged (22-24 months) Fischer 344 rats. Since M-1 AChRs are coupled to the metabolism of phosphoinositides, carbachol-induced accumulation of inositol phosphates (IP) and its inhibition by glutamate and NMDA was also measured in the cortical slices. DFP treatment caused about 75% inhibition of cholinesterase and 35% down-regulation of mAChRs (measured as [3H]quinuclidinyl benzylate binding) in both young and aged rats. The down-regulation of M-1-ACHRs (measured as [3H]pirenzepine binding) was more pronounced in aged (30%) than in young (17%) DFP-treated rats. There was a significant increase in carbachol-induced IP accumulation in aged, with respect to young, untreated rats. DFP treatment caused a considerable decrease in such IP accumulation in aged but not in young rats. Glutamate and NMDA antagonized carbachol-induced IP accumulation in untreated young and aged rats (and the effects of NMDA were reversed by carboxy-piperazinyl-propyl phosphonic acid). In DFP-treated rats such antagonism was somewhat less pronounced. The data appear of interest in relation to the use of anticholinesterase compounds in the therapy of senile dementia of Alzheimer's type. They suggest that beside their primary action (increasing brain ACh levels) such compounds also act on post-receptor mechanisms and on the interactions between cholinergic and glutamatergic neurotransmitter systems.

Effect of propylthiouracil-induced hypothyroidism on cerebral cortex of young and aged rats: lipid composition of synaptosomes, muscarinic receptor sites, and acetylcholinesterase activity.

The effect of hypothyroidism on the lipid composition of synaptosomes, density and affinity of muscarinic receptor sites, and acetylcholinesterase activity in the cerebral cortex of young and aged rats was investigated. The animals were made hypothyroid by adding 0.05% propyl-2-thiouracil to their drinking water for four weeks. This pathological state induced an increase in the relative percentage of sphingomyelin in young rats. In aged rats hypothyroidism induced a decrease of sphingomyelin and glycerophosphocholine and an increase of cholesterol. The effect of hypothyroid state on cerebral cortex resulted in an increase of acethylcholinesterase activity both in young and aged rats and was also reflected in an increase of density of M1-AChRs but only in the former.

Altered modulation by excitatory amino acids of cortical phosphatidylinositol system stimulated by carbachol in rats poisoned by an anti-cholinesterase compound, diisopropyl fluorophosphate.

The effects of glutamate and N-methyl aspartate (NMDA) on carbachol-induced inositol phosphate (IP) accumulation were evaluated in slices of the cerebral cortex of rats treated with diisopropyl fluorophosphate (DFP) for 2 weeks. This induced an about 75% inhibition of cholinesterases. The IP accumulation induced by carbachol (expressed as ratio stimulated/basal IP content) was lower in DFP rats than in controls when incorporation of [3H]-myoinositol into membrane phospholipids and their hydrolysis were measured (no washing step between labeling and hydrolytic incubation). There were no differences in carbachol induced IP accumulation between control and DFP rats when only phosphoinositide hydrolysis was determined (hydrolytic incubation of prelabeled washed slices). When both incorporation of [3H]-myoinositol and the hydrolysis were measured, 0.5 mM glutamate and 0.1 mM NMDA caused a significant, about 40%, decrease of carbachol-induced IP accumulation in control rats; the inhibitory effects of glutamate and NMDA were not significant in DFP rats. When only hydrolytic IP accumulation by carbachol was studied, the inhibitory effects of glutamate and NMDA were very similar in control and DFP rats. Additional experiments on inositol phospholipid synthesis showed a significantly lesser [3H]-myoinositol incorporation (by about 30%) in DFP rats. This may explain the differences between the results obtained by the two methods. The overall data suggest that the attenuation of glutamate and NMDA effects in DFP-rats depends on a decrease of carbachol-induced IP accumulation or phosphoinositide synthesis rather than on the EAA specific action.

Effects of excitatory amino acids on inositol phosphate accumulation in slices of the cerebral cortex of young and aged rats.

The effects of glutamate, NMDA and quisqualate on carbachol- and norepinephrine-elicited formation of inositol phosphate (IP) were evaluated in slices prepared from the cerebral cortex of 3- and 24-month Sprague-Dawley rats. Glutamate, NMDA, and quisqualate antagonized the IP response to carbachol in a concentration-dependent fashion. This antagonism was more pronounced in aged than in young rats, both for glutamate (IC5O 0.114 and 0.210 mM) and NMDA (IC5O 0.0029 and 0.127 mM), but not for quisqualate. Glutamate (but not NMDA) also antagonized in a concentration-dependent fashion the IP response to norepinephrine, IC50s were 0.061 and 0.126 mM for aged and young rats, respectively; quisqualate had an inhibitory effect only at 1 mM concentration in the two age-groups, while in aged rats some stimulatory effect was present at 0.1 mM concentration. Glutamate, NMDA and quisqualate (1 mM) did not affect basal IP accumulation in either young or aged rats; quisqualate, however, at 0.1 mM concentration had some stimulatory effect, more pronounced in aged rats. This effect was probably responsible for the biphasic effect of quisqualate in this age-group. The most important finding consists of the demonstration of an age-related increase in the inhibitory effects of NMDA on carbachol-induced IP accumulation. This implies an altered modulation of cholinergic post-receptor mechanisms by glutamatergic mechanisms.