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1.
Mol Psychiatry ; 27(3): 1339-1349, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34819636

RESUMO

The gabapentinoids, gabapentin, and pregabalin, target the α2δ subunits of voltage-gated calcium channels. Initially licensed for pain and seizures, they have become widely prescribed drugs. Many of these uses are off-label for psychiatric indications, and there is increasing concern about their safety, so it is particularly important to have good evidence to justify this usage. We conducted a systematic review and meta-analysis of the evidence for three of their common psychiatric uses: bipolar disorder, anxiety, and insomnia. Fifty-five double-blind randomised controlled trials (RCTs) and 15 open-label studies were identified. For bipolar disorder, four double-blind RCTs investigating gabapentin, and no double-blind RCTs investigating pregabalin, were identified. A quantitative synthesis could not be performed due to heterogeneity in the study population, design and outcome measures. Across the anxiety spectrum, a consistent but not universal effect in favour of gabapentinoids compared to placebo was seen (standardised mean difference [SMD] ranging between -2.25 and -0.25). Notably, pregabalin (SMD -0.55, 95% CI -0.92 to -0.18) and gabapentin (SMD -0.92, 95% CI -1.32 to -0.52) were more effective than placebo in reducing preoperative anxiety. In insomnia, results were inconclusive. We conclude that there is moderate evidence of the efficacy of gabapentinoids in anxiety states, but minimal evidence in bipolar disorder and insomnia and they should be used for these disorders only with strong justification. This recommendation applies despite the attractive pharmacological and genetic rationale for targeting voltage-gated calcium channels.


Assuntos
Transtorno Bipolar , Ácidos Cicloexanocarboxílicos , Distúrbios do Início e da Manutenção do Sono , Aminas/uso terapêutico , Ansiedade/tratamento farmacológico , Transtorno Bipolar/tratamento farmacológico , Canais de Cálcio , Ácidos Cicloexanocarboxílicos/uso terapêutico , Gabapentina/uso terapêutico , Humanos , Pregabalina/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Ácido gama-Aminobutírico/uso terapêutico
2.
Mol Psychiatry ; 26(8): 4106-4116, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-31801967

RESUMO

Calcium signalling has long been implicated in bipolar disorder, especially by reports of altered intracellular calcium ion concentrations ([Ca2+]). However, the evidence has not been appraised critically. We carried out a systematic review and meta-analysis of studies of cellular calcium indices in bipolar disorder. 2281 records were identified and 117 screened, of which 32 were eligible and 21 were suitable for meta-analyses. The latter each involved up to 642 patients and 404 control subjects. We found that basal free intracellular [Ca2+] is increased in bipolar disorder, both in platelets and in lymphocytes. The effect size is 0.55, with an estimated elevation of 29%. It is observed in medication-free patients. It is present in mania and bipolar depression, but data are equivocal for euthymia. Cells from bipolar disorder individuals also show an enhanced [Ca2+] response to stimulation with 5-HT or thrombin, by an estimated 25%, with an effect size of 0.63. In studies which included other diagnoses, intracellular basal [Ca2+] was higher in bipolar disorder than in unipolar depression, but not significantly different from schizophrenia. Functional parameters of cellular Ca2+ (e.g. calcium transients), and neuronal [Ca2+], have been much less investigated, and no firm conclusions can be drawn. In summary, there is a robust, medium effect size elevation of basal and stimulated free intracellular [Ca2+] in bipolar disorder. The results suggest altered calcium functioning in the disorder, and encourage further investigations into the underlying mechanisms, and the implications for pathophysiology and therapeutics.


Assuntos
Transtorno Bipolar , Transtorno Depressivo , Esquizofrenia , Plaquetas , Cálcio , Humanos
3.
J Pathol ; 229(4): 608-20, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23208928

RESUMO

Epidermal growth factor receptor (EGFR) pathway activation is a frequent event in human carcinomas. Mutations in EGFR itself are, however, rare, and the mechanisms regulating EGFR activation remain elusive. Leucine-rich immunoglobulin repeats-1 (LRIG1), an inhibitor of EGFR activity, is one of four genes identified that predict patient survival across solid tumour types including breast, lung, melanoma, glioma, and bladder. We show that deletion of Lrig1 is sufficient to promote murine airway hyperplasia through loss of contact inhibition and that re-expression of LRIG1 in human lung cancer cells inhibits tumourigenesis. LRIG1 regulation of contact inhibition occurs via ternary complex formation with EGFR and E-cadherin with downstream modulation of EGFR activity. We find that LRIG1 LOH is frequent across cancers and its loss is an early event in the development of human squamous carcinomas. Our findings imply that the early stages of squamous carcinoma development are driven by a change in amplitude of EGFR signalling governed by the loss of contact inhibition.


Assuntos
Caderinas/metabolismo , Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/genética , Glicoproteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Lesões Pré-Cancerosas/genética , Animais , Caderinas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Transformação Celular Neoplásica , Inibição de Contato , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica , Homeostase , Humanos , Perda de Heterozigosidade , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Complexos Multiproteicos , Proteínas do Tecido Nervoso/metabolismo , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Deleção de Sequência , Transdução de Sinais
4.
Angew Chem Int Ed Engl ; 53(46): 12466-70, 2014 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-25294680

RESUMO

DNA-based cytotoxic agents: Nanopores composed of folded DNA featuring a hydrophobic belt of ethyl phosphorothioate groups insert into bilayer membranes and kill cancer cells. The mode by which the pores achieve cell killing is elucidated with confocal microscopy.


Assuntos
Antineoplásicos/farmacologia , DNA/farmacologia , Nanoporos/ultraestrutura , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Citotoxinas/administração & dosagem , Citotoxinas/química , Citotoxinas/farmacologia , DNA/administração & dosagem , DNA/química , Humanos , Neoplasias/tratamento farmacológico
5.
CNS Drugs ; 36(1): 1-16, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34928485

RESUMO

The cognitive dysfunction experienced by patients with schizophrenia represents a major unmet clinical need. We believe that enhancing synaptic function and plasticity by targeting kalirin may provide a novel means to remediate these symptoms. Karilin (a protein encoded by the KALRN gene) has multiple functional domains, including two Dbl homology (DH) guanine exchange factor (GEF) domains, which act to enhance the activity of the Rho family guanosine triphosphate (GTP)-ases. Here, we provide an overview of kalirin's roles in brain function and its therapeutic potential in schizophrenia. We outline how it mediates diverse effects via a suite of distinct isoforms that couple to members of the Rho GTPase family to regulate synapse formation and stabilisation, and how genomic and post-mortem data implicate it in schizophrenia. We then review the current state of knowledge about the influence of kalirin on brain function at a systems level, based largely on evidence from transgenic mouse models, which support its proposed role in regulating dendritic spine function and plasticity. We demonstrate that, whilst the GTPases are classically considered to be 'undruggable', targeting kalirin and other Rho GEFs provides a means to indirectly modulate their activity. Finally, we integrate across the information presented to assess the therapeutic potential of kalirin for schizophrenia and highlight the key outstanding questions required to advance it in this capacity; namely, the need for more information about the diversity and function of its isoforms, how these change across neurodevelopment, and how they affect brain function in vivo.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Esquizofrenia/tratamento farmacológico , Disfunção Cognitiva/complicações , Humanos , Plasticidade Neuronal , Esquizofrenia/complicações
7.
Nanoscale ; 6(12): 7052-61, 2014 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-24842463

RESUMO

The assessment of the risks exerted by nanoparticles is a key challenge for academic, industrial, and regulatory communities worldwide. Experimental evidence points towards significant toxicity for a range of nanoparticles both in vitro and in vivo. Worldwide efforts aim at uncovering the underlying mechanisms for this toxicity. Here, we show that the intracellular ion release elicited by the acidic conditions of the lysosomal cellular compartment--where particles are abundantly internalized--is responsible for the cascading events associated with nanoparticles-induced intracellular toxicity. We call this mechanism a "lysosome-enhanced Trojan horse effect" since, in the case of nanoparticles, the protective cellular machinery designed to degrade foreign objects is actually responsible for their toxicity. To test our hypothesis, we compare the toxicity of similar gold particles whose main difference is in the internalization pathways. We show that particles known to pass directly through cell membranes become more toxic when modified so as to be mostly internalized by endocytosis. Furthermore, using experiments with chelating and lysosomotropic agents, we found that the toxicity mechanism for different metal containing NPs (such as metallic, metal oxide, and semiconductor NPs) is mainly associated with the release of the corresponding toxic ions. Finally, we show that particles unable to release toxic ions (such as stably coated NPs, or diamond and silica NPs) are not harmful to intracellular environments.


Assuntos
Apoptose/efeitos dos fármacos , Membrana Celular/química , Endocitose/fisiologia , Ouro/toxicidade , Nanopartículas Metálicas/toxicidade , Difusão , Relação Dose-Resposta a Droga , Ouro/química , Humanos , Nanopartículas Metálicas/química , Tamanho da Partícula
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