Biomedical subjects

A Bartolini

Publications and source records attributed to A Bartolini.

At least 19 recordsLinked to original sources

PubMed2004

Alpha-2 agonists induce amnesia through activation of the Gi-protein signalling pathway.

The post-receptorial mechanism of the amnesic action of the alpha2-agonists clonidine and guanabenz was investigated in the mouse passive avoidance test. Animals were i.c.v. injected with pertussis toxin (PTX) or with antisense oligonucleotides, complementary to the sequence of the alpha-subunit mRNA of Gi1, Gi2, Gi3, Go1 and Go2 proteins. The administration of PTX (0.25 microg per mouse i.c.v.) reversed the amnesia induced by both alpha2-agonists. Similarly, anti-Gialpha1 (6.25-12.5 microg per mouse i.c.v.), anti-Gialpha3 (3.12-12.5 microg per mouse i.c.v.), anti-Goalpha1 (12.5-25 microg per mouse i.c.v.) antagonised the detrimental effect induced by clonidine and guanabenz. By contrast, pretreatment with anti-Gialpha2 (3.12-25 microg per mouse i.c.v.) and anti-Goalpha2 (12.5-25 microg per mouse i.c.v.) never modified the impairment of memory processes induced by the alpha2-agonists. At the highest effective doses, none of the compounds used impaired motor coordination (rota rod test), nor modified spontaneous motility and inspection activity, (hole board test). These results indicate the involvement of Gi1, Gi3, and Go1, but not Gi2 and Go2, protein subtypes in the transduction mechanism responsible for the induction of amnesia by clonidine and guanabenz.

Adrenergic alpha-2 Receptor Agonists↗

PubMed2003

Anti-mu opioid antiserum against the third external loop of the cloned mu-opioid receptor acts as a mu receptor neutral antagonist.

The region from the third external loop to the C terminus of MOR-1 appeared to be critical to the selective binding of MOR-1 ligands as DAMGO and morphine to MOR-1. To study the pharmacological properties of the third extracellular loop an antibody was raised in rabbits against the sequence 304-316 which is unique to MOR-1 and includes the third external loop; the anti-MOR-1 antibody was affinity purified against the immunogen sequence and characterized by [3H]DAMGO and Western blotting; [3H]DPDPE binding assay remained unchanged in the presence of the antibody. Anti-MOR-1 IgG was characterized as a neutral antagonist in Chinese hamster ovary (CHO) cells hyperexpressing constitutively active MOR-1s; in fact, anti-MOR-1 IgG completely reversed the inhibition induced by the MOR-1 agonist endomorphin1, endomorphin2, DAMGO and morphine on forskolin stimulated cyclic AMP (cAMP) accumulation and attenuated both the action of the selective MOR-1 agonist DAMGO to increase [35S]GTPgammaS binding and the action of the MOR-1 inverse agonist beta-chlornaltrexamine (CNA) to decrease [35S]GTPgammaS binding. Radioligand binding assay using membrane suspensions from CHO cells hyperexpressing MOR-1 revealed a significant decreased binding affinity and capacity of all the tested MOR-1 selective ligands after preincubation with anti-MOR-1 IgG. Therefore, the third extracellular loop of MOR-1 appeared to be a key element for the binding of MOR-1 ligands.

Animals↗

PubMed2003

AMPA-receptor activation is involved in the antiamnesic effect of DM 232 (unifiram) and DM 235 (sunifiram).

DM 232 and DM 235 are novel antiamnesic compounds structurally related to ampakines. The involvement of AMPA receptors in the mechanism of action of DM 232 and DM 235 was, therefore, investigated in vivo and in vitro. Both compounds (0.1 mg/kg(-1) i.p.) were able to reverse the amnesia induced by the AMPA receptor antagonist NBQX (30 mg/kg(-1) i.p.) in the mouse passive avoidance test. At the effective doses, the investigated compounds did not impair motor coordination, as revealed by the rota rod test, nor modify spontaneous motility and inspection activity, as revealed by the hole board test. DM 232 and DM 235 reversed the antagonism induced by kynurenic acid of the NMDA-mediated release of [(3)H]NA in the kynurenate test performed in rat hippocampal slices. This effect was abolished by NBQX. DM 232 increases, in a concentration dependent manner, excitatory synaptic transmission in the rat hippocampus in vitro. These results suggest that DM 232 and DM 235 act as cognition enhancers through the activation of the AMPA-mediated neurotransmission system.

Amnesia↗

PubMed2003

Diphenhydramine-induced amnesia is mediated by Gi-protein activation.

The effect of the i.c.v. administration of antisense oligodeoxynucleotides directed against the alpha subunit of different Gi-proteins (anti-Gialpha(1), anti-Gialpha(2), anti-Gialpha(3), anti-Goalpha(1), anti-Goalpha(2)) on the amnesia induced by the H(1)-antihistamine diphenhydramine (20 mg kg(-1) s.c.) was evaluated in the mouse passive avoidance test. Pretreatment with anti-Gialpha(1) (12.5-25 microg per mouse i.c.v.) and anti-Gialpha(2) (25 microg per mouse i.c.v.), administered 24 and 18 h before test, prevented antihistamine-induced amnesia. By contrast, pretreatment with an anti-Gialpha(3) (25 microg per mouse i.c.v.), anti-Goalpha(1) (25 microg per mouse i.c.v.) and anti-Goalpha(2) (25 microg per mouse i.c.v.) did not modify the detrimental effect induced by diphenhydramine. At the highest effective doses, none of the compounds used impaired motor coordination, as revealed by the rota rod test, nor modified spontaneous motility and inspection activity, as revealed by the hole board test. These results suggest the important role played by the Gi(1)- and Gi(2)-protein pathway in the transduction mechanism involved in the impairment of memory processes produced by the H(1)-antihistamine diphenhydramine.

Amnesia↗

PubMed2002

DM235 (sunifiram): a novel nootropic with potential as a cognitive enhancer.

DM235 (sunifiram), a new compound structurally related to piracetam, prevented the amnesia induced by scopolamine (1.5 mg kg(-1) i.p.), after intraperitoneal (0.001-0.1 mg kg(-1)) or oral (0.01-0.1 mg kg(-1)) administration, as shown by a passive avoidance test in mice. The antiamnesic effect of DM235 was comparable to that of well-known nootropic drugs such as piracetam (30-100 mg kg(-1) i.p.), aniracetam (100 mg kg(-1) p.o.) or rolipram (30 mg kg(-1) p.o.). DM235 also prevented mecamylamine (20 mg kg(-1) i.p.)-, baclofen (2 mg kg(-1) i.p.)- and clonidine (0.125 mg kg(-1) i.p.)-induced amnesia in the same test. In the Morris water maze test with rats, scopolamine (0.8 mg kg(-1) i.p.) inhibited the reduction of escape latency in both acquisition and retention/retraining tests. DM235 (0.1 mg kg(-1) i.p.), 20 min before each daily acquisition training, prevented the scopolamine-induced memory impairment. DM235 (1 mg kg(-1) i.p.) also reduced the duration of pentobarbitone-induced hypnosis in mice without modifying the induction time of hypnosis. At the highest effective doses, the investigated compound neither impaired motor coordination (rota-rod test), nor modified spontaneous motility and inspection activity (Animex and hole board tests). These results indicate that DM235, a compound structurally related to piracetam, is a novel nootropic endowed with the capability to prevent cognitive deficits at very low doses. Indeed, its potency is about 1,000 times higher than that of the most active piracetam-like compounds.

Animals↗

PubMed2002

Antihistamine antinociception is mediated by Gi-protein activation.

The effect of the i.c.v. administration of antisense oligodeoxynucleotides directed against the alpha subunit of different Gi-proteins (anti-Gi alpha(1), anti-Gi alpha(2), anti-Gi alpha(3)) on the antinociception induced by the H(1)-antihistamines was evaluated in the mouse hot-plate test. The administration of diphenhydramine (20 mg kg(-1) s.c.), pyrilamine (15 mg kg(-1) s.c.) and promethazine (6 mg kg(-1) s.c.) produced an increase of the pain threshold which peaked 15 min after injection. Pretreatment with anti-Gi alpha(1) (12.5 microg per mouse i.c.v.), anti-Gi alpha(2) (25 microg per mouse i.c.v.) and anti-Gi alpha(3) (25 microg per mouse i.c.v.), administered 24 and 18 h before test, prevented the antihistamine-induced antinociception. At the highest effective doses, none of the compounds used impaired motor coordination, as revealed by the rota rod test, nor modified spontaneous motility and inspection activity, as revealed by the hole board test. These results suggest an important role played by the Gi-protein pathway in the transduction mechanism involved in the enhancement of the pain threshold produced by H(1)-antihistamines.

Analgesics↗

PubMed2002

Endogenous morphine modulates acute thermonociception in mice.

The endogenous synthesis of morphine has been clearly demonstrated throughout the phylogenesis of the nervous system of mammals and lower animals. Endogenous morphine, serving as either a neurotransmitter or neurohormone, has been demonstrated in the nervous system of both vertebrates and invertebrates. As one of the effects of exogenous morphine is the modulation of pain perception, we investigated the effects that the depletion of endogenous morphine had on nociceptive transmission. The immunoneutralization of endogenous morphine from brain extracellular spaces was obtained through the intracerebroventricular administration of affinity purified anti-morphine IgG to mice, which then underwent the hot plate test. Endogenous morphine immunoneutralization decreased thermal response latency and attenuated the anti-nociceptive effect of the mu selective agonist DAMGO in hot plate test suggesting that endogenous morphine is involved in pain modulation.

Acute Disease↗

PubMed2001

Structure-affinity relationships of a unique nicotinic ligand: N(1)-dimethyl-N(4)-phenylpiperazinium iodide (DMPP).

DMPP is a well-known nicotinic agonist that does not fit any proposed pharmacophore for nicotinic binding and represents a unique ligand among the hundreds of nicotinic agonists studied in the past decades. A systematic modulation of the chemical structure of DMPP, aimed to establish its structure-affinity relationships, is reported. The research has allowed to identify molecules such as 11c, 13c, 14c, and 28c, with affinities for alpha(4)beta(2) receptors in the low nanomolar range, some 2 orders of magnitude lower than the lead compound. The agonistic properties of the most interesting compounds have been assessed by measuring their analgesic activity on mice (hot-plate test). Another result of the research was the identification of DMPP analogues, such as 3a (K(i) = 90 nM) and 14b (K(i) = 180 nM), that maintain affinity for the central nicotinic receptor when the ammonium function is changed into an aminic one and are therefore possible leads for drug development in neurodegenerative diseases.

Analgesics↗

PubMed2001

Involvement of potassium channels in amitriptyline and clomipramine analgesia.

The effect of the administration of modulators of different subtypes of K(+) channels on antinociception induced by the tricyclic antidepressants amitriptyline and clomipramine was evaluated in the mouse hot plate test. The administration of the voltage-gated K(+) channel blocker tetraethylammonium (0.01-0.5 microg per mouse i.c.v. ) prevented antinociception induced by both amitriptyline (15 mg kg(-1) s.c.) and clomipramine (25 mg kg(-1) s.c.). The K(ATP) channel blocker gliquidone (0.1-1.0 microg per mouse i.c.v.) prevented antinociception produced by amitriptyline and clomipramine whereas the K(ATP) channel openers minoxidil (10 microg per mouse i. c.v.) and pinacidil (25 microg per mouse i.c.v.) potentiated tricyclic antidepressant-induced analgesia. The administration of the Ca(2+)-gated K(+) channel blocker apamin (0.1-1.0 ng per mouse i. c.v.) completely prevented amitriptyline and clomipramine analgesia. At the highest effective doses, none of the drugs used induced behavioural side effects or impaired motor coordination, as revealed by the rota-rod test, spontaneous motility or inspection activity, as revealed by the hole board test. The present results demonstrate that central antinociception induced by amitriptyline and clomipramine involves the opening of different subtypes of K(+) channels (voltage-gated, K(ATP) and Ca(2+)-gated) which, therefore, represent a step in the transduction mechanism of tricyclic antidepressant analgesia.

Amitriptyline↗

PubMed2001

Differential prevention of morphine amnesia by antisense oligodeoxynucleotides directed against various Gi-protein alpha subunits.

The effect of the i.c.v. administration of pertussis toxin (PTX) and antisense oligodeoxynucleotide directed against the alpha subunit of different Gi-proteins (anti-Gialpha1, anti-Gialpha2, anti-Gialpha3) on amnesia induced by morphine was evaluated in the mouse passive avoidance test. The administration of morphine (6 - 10 mg kg(-1) i.p.) immediately after the training session produced amnesia that was prevented by PTX (0.25 microg per mouse i.c.v.) administered 7 days before the passive avoidance test. Anti-Gialpha1 (6.25 microg per mouse i.c.v.) and anti-Gialpha3 (12.5 microg per mouse i.c.v.), administered 18 and 24 h before the training session, prevented the morphine amnesia. By contrast, pretreatment with anti-Gialpha2 (3.12 - 25 microg per mouse i.c.v.) never modified the impairment of memory processes induced by morphine. At the highest effective doses, none of the compounds used impaired motor coordination, as revealed by the rota rod test, nor modified spontaneous motility and inspection activity, as revealed by the hole board test. These results suggest the important role played by Gi1 and Gi3 protein subtypes in the transduction mechanism involved in the impairment of memory processes produced by morphine.

Amnesia↗

PubMed2001

Hypofunctionality of Gi proteins as aetiopathogenic mechanism for migraine and cluster headache.

The involvement of Gi proteins in the modulation of pain perception has been widely established, and mutations in G-proteins have already been identified as the aetiopathological cause of human diseases. The aim of the present study was to determine whether a deficiency or a hypofunctionality of the Gi proteins occurred in primary headache. The functionality and the level of expression of Gi proteins were investigated in lymphocytes from migraine without aura, migraine with aura and cluster headache sufferers. A reduced capability to inhibit forskolin-stimulated adenylyl cyclase activity in headache patients was observed. Migraine patients also showed basal adenosine cAMP levels about four times higher than controls. The reduced activity of Gi proteins seems not to be related to a reduction of protein levels since no significant reduction of the Gialpha subunits was observed. These results indicate Gi protein hypofunctionality as an aetiopathogenic mechanism in migraine and cluster headache.

Adult↗

PubMed2001

Local anaesthetic activity of (+)- and (-)-menthol.

In this work we studied the local anaesthetic activity of (+)- and (-)-menthol, a substance used after topical application to induce a feeling of coolness. We compared its activity to two chemically related compounds thymol and (-)-menthone. Anaesthetic activity was evaluated in vivo in the rabbit conjunctival reflex test and in vitro in a rat phrenic nerve hemidiaphragm preparation. Both enatiomers of menthol (10(-4)-1 micrograms/ml), but not thymol and (-)-menthone, were able to drastically reduce, in a dose-dependent manner, the electrically evoked contractions of rat phrenic hemidiaphragm. In the rabbit conjunctival reflex test, treatment with a solution of (+)- and (-)-menthol (30-100 micrograms/ml) allowed a dose-dependent increase in the number of stimuli necessary to provoke the reflex, thus confirming in vivo the local anaesthetic activity observed in vitro. Similar to the in vitro results, thymol and (-)-menthone were ineffective also in the in vivo test. In conclusion, these data evidence the local anaesthetic activity of menthol, which appears to be strictly dependent on its chemical structure.

Anesthetics, Local↗

PubMed2001

A reduced functionality of Gi proteins as a possible cause of fibromyalgia.

OBJECTIVE: The etiopathogenesis of fibromyalgia (FM), a syndrome characterized by widespread pain and hyperalgesia, is still unknown. Since the involvement of Gi proteins in the modulation of pain perception has been widely established, the aim of the present study was to determine whether an altered functionality of the Gi proteins occurred in patients with FM. METHODS: Patients with FM and other painful diseases such as neuropathic pain, rheumatoid arthritis (RA), and osteoarthritis, used as reference painful pathologies, were included in the study. The functionality, evaluated as capability to inhibit forskolin-stimulated adenylyl cyclase activity, and the level of expression of Gi proteins were investigated in peripheral blood lymphocytes. RESULTS: Patients with FM showed a hypofunctionality of the Gi protein system. In contrast, unaltered Gi protein functionality was observed in patients with neuropathic pain, RA, and osteoarthritis. Patients with FM also showed basal cAMP levels higher than controls. The reduced activity of Gi proteins seems to be unrelated to a reduction of protein levels since only a slight reduction (about 20-30%) of the Gi3alpha subunit was observed. CONCLUSIONS: Gi protein hypofunctionality is the first biochemical alteration observed in FM that could be involved in the pathogenesis of this syndrome. In the complete absence of laboratory diagnostic tests, the determination of an increase in cAMP basal levels in lymphocytes, together with the assessment of a Gi protein hypofunctionality after adenylyl cyclase stimulation, may lead to the biochemical identification of patients with FM.

Adenylyl Cyclases↗

PubMed2000

Molecular simplification of 1,4-diazabicyclo[4.3.0]nonan-9-ones gives piperazine derivatives that maintain high nootropic activity.

Several 4-substituted 1-acylpiperazines, obtained by molecular simplification of 4-substituted 1,4-diazabicyclo[4.3.0]nonan-9-ones, have been synthesized and tested in vivo on the mouse passive avoidance test, to evaluate their nootropic activity. The results show that, apparently, an N-acylpiperazine group can mimic the 2-pyrrolidinone ring of 1,4-diazabicyclo[4.3.0]nonan-9-one, as the compounds of the new series maintain high nootropic activity. Moreover molecular simplification produces more clear-cut structure-activity relationships with respect to the parent series. The mechanism of action also appears to be similar in the two series. In fact, although the molecular mechanism remains to be elucidated, the most potent compound of each class (DM232 and 13, DM235) is able to increase acetylcholine release in rat brain. Piperazine derivatives represent a new class of nootropic drugs with an in vivo pharmacological profile very similar to that of piracetam, showing much higher potency with respect to the reference compound. Among the compounds studied, 13 (DM235) shows outstanding potency, being active at a dose of 0.001 mg kg(-1) sc.

Acetylcholine↗

PubMed2000

Antiamnesic effect of metoprine and of selective histamine H(1) receptor agonists in a modified mouse passive avoidance test.

The aim of this study was to elucidate the effect caused by the inhibition of histamine catabolism by means of metoprine and the activation of histamine H(1) receptors by selective agonists on learning and memory processes, using a modified method of the mouse passive avoidance test. The administration of scopolamine 1 mg/kg (i. p.) immediately after the training session caused statistically-significant amnesia during the retention trial performed 24 h later. Piracetam (30 mg/kg (i.p.)), used as a positive control, and administered 20 min before the training session, prevented scopolamine-induced memory impairment. The histamine-N-methyltransferase inhibitor, metoprine, (2 and 5 mg/kg (s.c.)) had effects similar to those of this nootropic drug. The highly-selective H(1) receptor agonist, 2-(3-trifluoromethylphenyl)histamine (FMPH) (2.65 and 6.5 microg/mouse (i.c.v.)) and the less selective agonist, 2-thiazolylethylamine (2-TEA) (0.1 and 0.3 microg/mouse (i.c.v.)) both antagonized the scopolamine-induced amnesia significantly and in a dose-related manner. The selective H(1) receptor antagonist, pyrilamine (20 mg/kg (i.p.)), revealed no effect by itself, but significantly prevented the antiamnesic action both that of the H(1) receptor agonists, and that of endogenous histamine, released by metoprine, thus suggesting a cognitive improvement via the activation of H(1) receptors.

Amnesia↗

PubMed2000

Design, synthesis, and preliminary pharmacological evaluation of 1, 4-diazabicyclo[4.3.0]nonan-9-ones as a new class of highly potent nootropic agents.

Several 4-substituted 1,4-diazabicyclo[4.3.0]nonan-9-ones have been synthesized and tested in vivo on mouse passive avoidance test, to evaluate their nootropic activity. The results show that they represent a new class of nootropic drugs with a pharmacological profile very similar to that of piracetam, showing much higher potency with respect to the reference. Among the compounds studied, 7 (DM 232) shows outstanding potency, being active at the dose of 0. 001 mg kg(-1) sc.

Adrenergic alpha-Agonists↗

PubMed2000

Pharmacological identification of SM-21, the novel sigma(2) antagonist.

SM-21 is a tropane analogue with high affinity and selectivity for sigma(2) receptor subtype. In the absence of highly selective sigma(2) antagonists, the aim of the present study was to determine whether SM-21 is endowed with antagonistic activity. The experiments were conducted in rats by inducing neck dystonia, which is reported to be subsequent to activation of sigma(2) receptors. SM-21 (10 nmol/0.5 microl) was able to prevent torsion of the neck obtained by administration of the sigma(1)-sigma(2) agonist 1,3-di-(2-tolyl)guanidine (DTG, 5 nmol/0.5 microl) in the red nucleus. These data indicate that SM-21 is a potent and selective sigma(2) antagonist.

Analgesics↗

PubMed2000

Pro-cognitive activity induced in the rat by low doses of R-(+)-hyoscyamine.

In the passive-avoidance test R-(+)-hyoscyamine (10-100 microg kg(-1) i.p.) prevented amnesia induced by antimuscarinic treatment with AF-64A and benzhexol. The antiamnesic effect of R-(+)-hyoscyamine was comparable to that exerted by the cholinesterase inhibitor physostigmine (0.2 mg kg(-1) i.p) and the M(1) selective agonist AF-102B (10 mg kg(-1) i.p.). In the social learning test, R-(+)-hyoscyamine (10-100 microg kg(-1) i.p.) in adults rats, reduced the duration of active exploration of the familiar partner in the second session of the test similar to the nootropic drug piracetam (30 mg kg(-1) i.p.). These results demonstrated the ability of R-(+)-hyoscyamine to modulate memory functions and suggest that R-(+)-hyoscyamine could be useful in the treatment of cognitive deficits.

Amnesia↗