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Biomedical subjects

R Guerrini

Publications and source records attributed to R Guerrini.

At least 37 records · Page 2Linked to original sources
PubMed2003

Assessment of the activity of a novel nociceptin/orphanin FQ analogue at recombinant human nociceptin/orphanin FQ receptors expressed in Chinese hamster ovary cells.

The neuropeptide nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand for the nociceptin receptor (NOP). In an attempt to identify high potency NOP agonists for use in the brain we have compared the activity of a novel N/OFQ analogue [Phe(1)Psi(CH(2)-O)Gly(2)]N/OFQ(1-13)NH(2) ([F/G-O]) with the existing [Phe(1)Psi(CH(2)-NH)Gly(2)]N/OFQ(1-13)NH(2) ([F/G]). Both peptides are modified between the first two N-terminal amino acids and are further compared with the agonist template N/OFQ(1-13)NH(2) in [(3)H]N/OFQ binding, GTPgamma[(35)S] binding and cAMP inhibition studies using Chinese hamster ovary cells expressing the recombinant human NOP. All peptides displaced [(3)H]N/OFQ, stimulated GTPgamma[(35)S] binding and inhibited cAMP formation. In [(3)H]N/OFQ binding and GTPgamma[(35)S] binding the rank order affinity and potency was N/OFQ(1-13)NH(2)>[F/G-O]>[F/G]. In GTPgamma[(35)S] binding [F/G] was a clear partial agonist with intrinsic activity (E(max) stimulation factor, mean+/-SEM, n=4) of 7.75+/-1.02 compared with N/OFQ(1-13)NH(2) of 11.13+/-1.76. The efficacy of [F/G-O] (10.17+/-1.88) approached that of the full agonist N/OFQ(1-13)NH(2). Downstream, at the level of cAMP formation, all peptides were full agonists with the following rank order potency: N/OFQ(1-13)NH(2)>[F/G-O]=[F/G]. The enhanced potency and intrinsic activity of the novel [F/G-O] modification makes this an interesting peptide for further in vivo analysis.

Animals↗
PubMed2003

Spectrum of SCN1A mutations in severe myoclonic epilepsy of infancy.

OBJECTIVES: SCN1A mutations were recently reported in several patients with severe myoclonic epilepsy in infancy (SMEI). The authors analyzed SCN1A mutations in 93 patients with SMEI and made genotype-phenotype correlation to clarify the role of this gene in the etiology of SMEI. METHODS: All patients fulfilled the criteria for SMEI. The authors analyzed all patients for SCN1A mutations using denaturing high performance liquid chromatography. If a patient's chromatogram was abnormal, the authors sequenced the gene in the patient and both parents. RESULTS: SCN1A mutations were identified in 33 patients (35%). Most mutations were de novo, but were inherited in three patients. Parents carrying the inherited mutations had either no symptoms or a milder form of epilepsy. A greater frequency of unilateral motor seizures was the only clinical difference between patients with SCN1A mutations and those without. Truncating mutations were more frequently associated with such seizures than were missense mutations. The percentage of cases with family history of epilepsy was significantly higher in patients with SCN1A mutations. CONCLUSIONS: Unilateral motor seizures may be a specific clinical characteristic of SMEI caused by SCN1A mutations. Ten percent of SCN1A mutations are inherited from an asymptomatic or mildly affected parent, suggesting that SMEI is genetically heterogeneous. The increased frequency of familial epilepsy indicates that other genetic factors may contribute to this disorder.

Adult↗
PubMed2003

Facial hemangioma and cerebral corticovascular dysplasia: a syndrome associated with epilepsy.

The authors performed imaging studies in two children with epilepsy and congenital facial hemangioma. The first patient had dysplastic pericallosal arteries and frontal polymicrogyria. In the second patient, dysplastic arteries and dysplastic cortex lined the interhemispheric fissure, the dysplastic cortex bridging across the midline, which resulted in holoprosencephaly. Abnormal cortical development may underlie epilepsy in children with facial hemangioma.

Adolescent↗
PubMed2003

UFP-101, a high affinity antagonist for the nociceptin/orphanin FQ receptor: radioligand and GTPgamma(35)S binding studies.

Studies of the pharmacology of nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) have been hampered by the lack of a range of high potency antagonists. In this study we have examined the effects of a novel N/OFQ analogue [Nphe(1),Arg(14),Lys(15)]N/OFQ NH(2) hereafter referred to as UFP-101. [(3)H]N/OFQ competition binding and GTPgamma(35)S binding assays were performed using CHO cells expressing the human NOP receptor (CHO(hNOP)). UFP-101 (pK(i) of 10.14+/-0.09) and a range of NOP selective agonists displaced [(3)H]N/OFQ binding with the following rank order of affinity: [Arg(14),Lys(15)]N/OFQ>[( pF)Phe(4)]N/OFQ(1-13)NH(2)>N/OFQ(1-13)NH(2)>UFP-101>N/OFQ>Ro64-6198>[Nphe(1)]N/OFQ(1-13)NH(2). N/OFQ, N/OFQ(1-13)NH(2), [( pF)Phe(4)]N/OFQ(1-13)NH(2), [Arg(14),Lys(15)]N/OFQ and Ro64-6198 also produced a concentration dependent (pEC(50) values of 8.75+/-0.11, 9.28+/-0.15, 9.69+/-0.04, 9.12+/-0.11 and 8.09+/-0.07 respectively) and saturable stimulation of GTPgamma(35)S binding and all were full agonists. UFP-101 did not stimulate GTPgamma(35)S binding per se, but produced a concentration dependent and parallel rightward shift in the concentration response curves to all agonists. UFP-101 yielded pA(2) values in the range 8.4-9.0. For comparison a pA(2) for [Nphe(1)]N/OFQ(1-13)NH(2) (the template for UFP-101) against N/OFQ of 7.33+/-0.08 was obtained. Slope factors for the Schild regression lines were approximately 1 indicating competitivity. When UFP-101 is compared with its template molecule [Nphe(1)]N/OFQ(1-13)NH(2), Arg(14),Lys(15) substitution produced approximately 1 log greater potency. We suggest that due to its high potency UFP-101 should prove a further useful tool in the evaluation of the N/OFQ-NOP receptor system.

Animals↗
PubMed2003

Blockade of nociceptin/orphanin FQ-NOP receptor signalling produces antidepressant-like effects: pharmacological and genetic evidences from the mouse forced swimming test.

Nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the NOP receptor, regulates several central functions such as pain transmission, learning and memory, fear and anxiety and feeding and locomotor activity. It has been recently reported that NOP receptor antagonists induce antidepressant-like effects in the mouse forced swimming test (FST), i.e. reduce immobility time. This assay was used in the present study for further investigating the involvement of the NOP receptor in depression states. In male Swiss mice, intracerebroventricular injection (i.c.v) of the novel NOP receptor antagonist, UFP-101 (1-10 nmol) dose-dependently reduced the immobility time (control 192 +/- 14 s, UFP-101 91 +/- 15 s). The effect of 3 or 10 nmol UFP-101 was fully or partially reversed, respectively, by the coadministration of 1 nmol N/OFQ, which was inactive per se. NOP receptor knockout mice showed a reduced immobility time compared with their wild-type littermates (wild-type 215 +/- 10 s, knockout 143 +/- 12 s). Moreover, i.c.v. injected UFP-101 (10 nmol) significantly reduced immobility time in wild-type mice but not in NOP receptor knockout animals. In conclusion, these results, obtained using a combined pharmacological and genetic approach, indicate that blockade of the N/OFQ-NOP receptor signalling in the brain produces antidepressant-like effects in the mouse FST. These findings support the NOP receptor as a candidate target for the development of innovative antidepressant drugs.

Animals↗
PubMed2003

Characterization of brain malformations in the Baraitser-Winter syndrome and review of the literature.

Baraitser-Winter syndrome is a rare autosomal recessive disorder characterized by developmental delay, dysmorphic features, and multiple malformations also involving the brain. We report a further case and provide updated information about an unrelated girl reported in the original paper by Baraitser and Winter. Both of them presented with pachygyria and the latter case was recently found to have subcortical band heterotopia on high resolution brain MRI imaging. These two patients and a review of the previously reported cases indicate that a specific pattern of brain anomalies falling in the agyria-pachygyria-band spectrum is associated with this dysmorphic syndrome, which may be considered another example of syndromic neuronal migration defect.

Abnormalities, Multiple↗
PubMed2003

Abnormal corticomuscular and intermuscular coupling in high-frequency rhythmic myoclonus.

Frequency analysis may have some advantages over back-averaging in the neurophysiological assessment of patients with suspected cortical myoclonus in whom myoclonic EMG bursts repeat rhythmically at high frequency. However, the clinical utility of EEG-EMG coherence and related EMG-EMG coherence is not established. Equally, there is an incomplete understanding of the physiology of the systems contributing to the coherence evident between signals in cortical myoclonus. Here we address these issues in an investigation of EEG-EMG and EMG-EMG coupling in proximal and distal muscles of the upper extremities in nine patients with multifocal high frequency rhythmic myoclonus due to non-progressive conditions. We found exaggerated coherence between EEG and contralateral EMG and between pairs of ipsilateral EMG signals. The results of frequency analysis of EMG-EMG mirrored those for EEG-EMG, but the former technique was superior in distinguishing a pathologically exaggerated common drive in distal upper limb muscles. Both techniques were more sensitive than back-averaging. Frequency analysis also revealed important disparities between proximal and distal upper limb muscles. In the latter case, the functional coupling between cortex and muscle was dominated by efferent processes. In contrast, there was considerable inter-individual variation in the extent to which EEG-EMG and EMG-EMG coupling in proximal muscles reflected afferent and efferent loops. Thus, the processes sustaining myoclonic discharges may differ for proximal and distal muscles and between patients.

Adult↗
PubMed2002

Pharmacological profile of hemokinin 1: a novel member of the tachykinin family.

Recently, the cloning of a novel preprotachykinin gene (PPT-C) has been reported. This gene codes for a novel peptide named hemokinin 1 (HK-1). In contrast with the known tachykinins, which are exclusively expressed in neuronal tissues, PPT-C mRNA was detected primarily in hematopoietic cells. In this study, we pharmacologically characterised the effects of HK-1 using three tachykinin monoreceptor systems, namely the rabbit jugular vein (rbJV) for NK(1), the rabbit pulmonary artery (rbPA) for NK(2), and rat portal vein (rPV) for NK(3) receptors. In all these preparations substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) elicited concentration dependent contractions showing similar maximal effects and the following rank order of potency: SP > NKA = NKB in the rbJV, NKA > NKB >> SP in the rbPA, and NKB > NKA > SP in the rPV. In those vessels HK-1 behaved as a full agonist displaying potencies similar (rbPA and rPV) or slightly higher (rbJV) than those of SP. In the rbJV, SR 140333, a selective NK(1) receptor antagonist, antagonised the effects of HK-1 and SP with similar high potencies (pK(B) 9.3 and 9.5, respectively). Similar results were obtained with the pseudopeptide NK(1) antagonist, MEN 11467 (pK(B) 8.8 and 8.6, respectively). Taken together, these data indicate that HK-1 behaves as a NK(1) preferring receptor agonist.

Animals↗
PubMed2002

Familial periventricular heterotopia: missense and distal truncating mutations of the FLN1 gene.

OBJECTIVE: To examine the clinical and MRI associations in bilateral periventricular nodular heterotopia (BPNH) (MIM # 300049) in two families segregating a missense mutation and a C-terminal deletion of the filamin 1(FLN1) gene. BACKGROUND: Classical familial BPNH, an X-linked dominant disorder, has been associated with protein truncations or splicing mutations, which tend to cluster at the N-terminal of the FLN1 protein, causing severe predicted loss of the protein function. The clinical syndrome includes symmetrical contiguous nodular heterotopia lining the lateral ventricles, epilepsy, mild retardation to normal cognitive level in affected females, and prenatal lethality in hemizygous boys. METHODS: Clinical examination, cognitive testing, MRI, mutation analysis (direct sequencing, single-strand conformation polymorphism) in seven patients from two families with BPNH. RESULTS: In Family 1, harboring an A > T change in exon 2 (E82V), heterotopic nodules were few, asymmetric, and noncontiguous. Five boys born from affected females had died unexpectedly early in life. In Family 2, harboring an 8 base pair deletion in exon 47 (7627_7634del TGTGCCCC), heterotopic nodules were thick and contiguous. Affected females in both families showed normal to borderline IQ and epilepsy. CONCLUSION: Missense mutations and distal truncations consistent with partial loss of FLN1 function cause familial BPNH with the classical clinical phenotype including epilepsy and mild mental retardation, if any. However, missense mutations have milder anatomic consequences in affected females and are possibly compatible with live birth but short survival of boys.

Abortion, Spontaneous↗
PubMed2002

Nociceptin/orphanin FQ receptors modulate glutamate extracellular levels in the substantia nigra pars reticulata. A microdialysis study in the awake freely moving rat.

Intracerebral microdialysis was employed in awake freely moving rats to investigate the effects of nociceptin/orphanin FQ receptor ligands on glutamate extracellular levels in the substantia nigra pars reticulata. Nociceptin/orphanin FQ, ineffective at 0.1 microM, induced a prolonged stimulation of nigral glutamate levels at 1 and 10 microM (mean effect of 137+/-9 and 167+/-13%, respectively, of basal values). These effects were prevented by the novel nociceptin/orphanin FQ receptor antagonist [Nphe(1)]nociceptin/orphanin FQ(1-13)NH(2) (100 and 300 microM, respectively) but not by the non-selective opioid receptor antagonist naloxone (10 microM). [Nphe(1)]nociceptin/orphanin FQ(1-13)NH(2) (100 microM) inhibited by itself glutamate outflow (maximal reduction to 71+/-4%) while naloxone was ineffective. The nociceptin/orphanin FQ receptor ligand [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin/orphanin FQ(1-13)NH(2) also facilitated glutamate outflow at 10 microM (mean effect of 145+/-10%). Intranigral perfusion with tetrodotoxin (1 microM) or with the dopamine D(2) receptor antagonist raclopride (1 microM), failed to affect basal glutamate output and prevented the facilitatory effect of nociceptin/orphanin FQ (10 microM). However, perfusion with the GABA(A) receptor antagonist bicuculline (10 microM) increased local glutamate extracellular levels by itself and attenuated the effect of the peptide. Our data suggest that nociceptin/orphanin FQ increases glutamate extracellular levels in the substantia nigra pars reticulata via activation of nociceptin/orphanin FQ receptors located on non-glutamatergic, possibly dopaminergic and GABAergic, neuronal elements.

Animals↗
PubMed2002

Intravenous immunoglobulin in neurological disease: a specialist review.

Treatment of neurological disorders with intravenous immunoglobulin (IVIg) is an increasing feature of our practice for an expanding range of indications. For some there is evidence of benefit from randomised controlled trials, whereas for others evidence is anecdotal. The relative rarity of some of the disorders means that good randomised control trials will be difficult to deliver. Meanwhile, the treatment is costly and pressure to "do something" in often distressing disorders considerable. This review follows a 1 day meeting of the authors in November 2000 and examines current evidence for the use of IVIg in neurological conditions and comments on mechanisms of action, delivery, safety and tolerability, and health economic issues. Evidence of efficacy has been classified into levels for healthcare interventions (tables 1 and 2).

Drug Costs↗
PubMed2001

Classification system for malformations of cortical development: update 2001.

The many recent discoveries concerning the molecular biologic bases of malformations of cortical development and the discovery of new such malformations have rendered previous classifications out of date. A revised classification of malformations of cortical development is proposed, based on the stage of development (cell proliferation, neuronal migration, cortical organization) at which cortical development was first affected. The categories have been created based on known developmental steps, known pathologic features, known genetics (when possible), and, when necessary, neuroimaging features. In many cases, the precise developmental and genetic features are uncertain, so classification was made based on known relationships among the genetics, pathologic features, and neuroimaging features. A major change since the prior classification has been the elimination of the separation between diffuse and focal/multifocal malformations, based on the recognition that the processes involved in these processes are not fundamentally different; the difference may merely reflect mosaicism, X inactivation, the influence of modifying genes, or suboptimal imaging. Another change is the listing of fewer specific disorders to reduce the need for revisions; more detail is added in other smaller tables that list specific malformations and malformation syndromes. This classification is useful to the practicing physician in that its framework allows a better conceptual understanding of the disorders, while the component of neuroimaging characteristics allows it to be applied to all patients without necessitating brain biopsy, as in pathology-based classifications.

Brain↗
PubMed2001

Studies on the antinociceptive effect of [Nphe1]nociceptin(1-13)NH2 in mice.

Nociceptin/orphanin FQ (NC) and its receptor (OP(4)) have been implicated in the regulation of various functions including nociception. [Nphe(1)]NC(1-13)NH(2) (Nphe) is a selective OP(4) antagonist which prevents the pronociceptive effects of supraspinal NC and causes per se a naloxone-insensitive antinociceptive effect. In the present study, we tested Nphe in wild type (WT) and OP(4) receptor knock out mice and found that a clear antinociceptive effect of the antagonist was evident only in WT mice. Moreover, we evaluated, over 5 days of treatment, the antinociceptive effects of Nphe in comparison with those of DAMGO and found that tolerance develops to the effects of the opioid receptor agonist but not to Nphe. These data demonstrate that the antinociceptive action of Nphe is due to the block of OP(4) receptors and that no tolerance develops to this kind of antinociception.

Analgesics↗
PubMed2001

Structure-activity studies of the Phe(4) residue of nociceptin(1-13)-NH(2): identification of highly potent agonists of the nociceptin/orphanin FQ receptor.

A total of 32 compounds was prepared to investigate the functional role of Phe(4) in NC(1-13)-NH(2), the minimal sequence maintaining the same activity as the natural peptide nociceptin. These compounds could be divided into three series in which Phe(4) was replaced with residues that would (i) alter aromaticity or side chain length, (ii) introduce steric constraint, and (iii) modify the phenyl ring. Compounds were tested for biological activity as (a) inhibitors of the electrically stimulated contraction of the mouse vas deferens; (b) competitors of the binding of [(3)H]-NC-NH(2) to mouse brain membranes; and (c) inhibitors of forskolin-stimulated cAMP accumulation in CHO cells expressing the recombinant human OP(4) receptor. Results indicate that all compounds of the first and second series were inactive or very weak with the exception of [N(CH(3))Phe(4)]NC(1-13)-NH(2), which was only 3-fold less potent than NC(1-13)-NH(2). Compounds of the third series showed higher, equal, or lower potencies than NC(1-13)-NH(2). In particular, [(pF)Phe(4)]NC(1-13)-NH(2) (pF) and [(pNO(2))Phe(4)]NC(1-13)-NH(2) (pNO(2)) were more active than NC(1-13)-NH(2) by a factor of 5. In the mVD, these compounds showed the following order of potency: (pF) = (pNO(2)) > or = (pCN) > (pCl) > (pBr) > (pI) = (pCF(3)) = (pOCH(3)) > (pCH(3)) > (pNH(2)) = (pOH). (oF) and especially (mF) maintained high potencies but were less active than (pF). Similar orders of potency were observed in binding competition and cAMP accumulation studies. There was a strong (r(2) > or = 0.66) correlation between data observed in these assays. Biological activity data of compounds of the third series were plotted against some Hansch parameters that are currently used to quantify physicochemical features of the substituents. In the three biological assays agonist potency/affinity positively correlates with the electron withdrawal properties of the groups in the p-position of Phe(4) and inversely with their size.

Animals↗
PubMed2001

Endogenous nociceptin signaling and stress-induced analgesia.

Nociceptin/orphanin FQ (NC) and its receptor (OP4) have been implicated in pain transmission. The aim of the present study was to investigate the role of the NC/OP4 system in stress-induced analgesia (SIA). The tail-withdrawal assay was performed in mice stressed by forced swimming in water at 15 degrees C (high severity swims) or 32 degrees C (low severity swims). High severity swims produced a naloxone-insensitive antinociceptive effect which was blocked by supraspinal NC (1 nmol). The selective OP4 receptor antagonist, [Nphe1]NC(-13)NH2 (30 nmol), was inactive by itself, but prevented the effect of NC. Low severity swims produced a milder analgesic effect that was partially antagonized by naloxone, completely blocked by NC and potentiated by [Nphe1]NC(-13)NH2. These findings confirm the anti-analgesic role of supraspinal NC and suggest that endogenous NC signaling counteracts the opioid component of SIA.

Analgesia↗
PubMed2001

Inhibition of human multidrug resistance P-glycoprotein 1 by analogues of a potent delta-opioid antagonist.

Analogues Dmt-Tic (2',6'-dimethyl-L-tyrosine-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) pharmacophore, a potent delta-opioid receptor antagonist, inhibited hMDR1 P-GP expressed in a G-185 fibroblast cell line in a manner similar to verapamil. N,N(Me)2-Dmt-Tic-NH-1-adamantane, H-Dmt-Tic-NH-1-adamantane, H-Dmt-Tic-Ala-NH-1-adamantane and N,N(Me)2-Dmt-Tic-NH-tBut were highly effective inhibitors. Weaker inhibition was observed with N,N(Et)2-Dmt-Tic-OH, H-Dmt-Tic-Ala-NH-tert-butyl amide and cyclo(Dmt-Tic). Results demonstrate that N- and C-terminal hydrophobic/lipophilic analogues of the Dmt-Tic pharmacophore inhibit hMDR1 and point to a potential role as chemosensitizing agents in chemotherapy for cancers containing hMDR1.

3T3 Cells↗