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1.
Molecules ; 26(2)2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33467760

RESUMO

For effective Auger therapy of cancer, the Auger-electron emitters must be delivered to the tumor cells in close proximity to a radiosensitive cellular target. Nuclear DNA is considered the most relevant target of Auger electrons to have augmented radiotoxic effects and significant cell death. However, there is a growing body of evidence that other targets, such as the mitochondria, could be relevant subcellular targets in Auger therapy. Thus, we developed dual-targeted 99mTc(I) tricarbonyl complexes containing a triphenylphosphonium (TPP) moiety to promote accumulation of 99mTc in the mitochondria, and a bombesin peptide to provide specificity towards the gastrin releasing peptide receptor (GRPr) overexpressed in prostate cancer cells. The designed dual-targeted complex, 99mTc-TPP-BBN, is efficiently internalized by human prostate cancer PC3 cells through a specific GRPr-mediated mechanism of uptake. Moreover, the radioconjugate provided an augmented accumulation of 99mTc in the mitochondria of the target tumor cells, most probably following its intracellular cleavage by cathepsin B. In addition, 99mTc-TPP-BBN showed an enhanced ability to reduce the survival of PC3 cells, in a dose-dependent manner.


Assuntos
Bombesina/farmacologia , Mitocôndrias/efeitos dos fármacos , Neoplasias da Próstata/radioterapia , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacologia , Tecnécio/farmacologia , Animais , Bombesina/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos da radiação , Humanos , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neurotransmissores/química , Neurotransmissores/farmacologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Receptores da Bombesina/metabolismo , Tecnécio/química
2.
Ecotoxicol Environ Saf ; 209: 111820, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33385678

RESUMO

The objective of this study was to investigate the influence of deltamethrin (DLM)on brain function and to find whether DLM-induced neurotoxicity is prevented by the treatment with cinnamon oil. Four groups of ten Wistar albino male rats each were used. Group I (control) received saline only. Group II received cinnamon oil alone at 0.5 mg/kg B.W. intraperitonally, whereas Group III received orally DLM alone at 6 mg/kg B.W. Groups IV was treated with cinnamon oil plus DLM for 21 days to induce neurotoxicity. Rat behaviour, brain acetylcholine esterase (AChE), serotonin, oxidative stress profile were assessed. Serum sampling for the assessment of corticosterone concentration was also carried out. Finally, we demonstrate the gene expression of CYP1A1 and iNOS and the histological picture of the brain. Considering the behaviour assessment, DLM administration alone caused neurobehavioral deficits manifested by anxiety-like behavior which represented ina marked decrease in the sleeping frequency and duration, and marked increase the digging frequency and a wake non-active behavior duration. Moreover, the open field result showed a significant decrease in central square entries and duration. The neurochemical analysis revealed that DLM significantly suppressed AChE activity and elevated serotonin and corticosterone concentrations. Furthermore, results revealed thatthe brain reduced glutathione (GSH) content, superoxide dismutase (SOD) activity and malondialdehyde (MDA) concentration were significantly altered in DLM treated rats. Neurochemical disturbances were confirmed by histopathological changes in the brain. Furthermore, DLM up-regulates the mRNA expression of brain CYP1A1 and iNOS. Co-treatment with cinnamon oil exhibited significant improvement in behavioural performance and the brain antioxidant capacities with an increase in AChE activity and diminished the concentration of serotonin, serum corticosterone and MDA. Cinnamon oil treatment resulted in down-regulation of CYP1A1 and iNOS and improve the histologically picture. In conclusion, cinnamon oil ameliorated DLM-induced neurotoxicity through preventing oxidative stress-induced genotoxicity and apoptosis of brain in rats.


Assuntos
Cinnamomum zeylanicum , Citocromo P-450 CYP1A1/metabolismo , Inseticidas/toxicidade , Neurotransmissores/farmacologia , Nitrilos/toxicidade , Óleos Voláteis/farmacologia , Piretrinas/toxicidade , Animais , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Glutationa/metabolismo , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
3.
Artigo em Inglês | MEDLINE | ID: mdl-32942346

RESUMO

Introduction: Bipolar disorder is a complex mood disorder characterized by a chronic and subtle course of fluctuating manic/hypomanic and depressive symptoms. Cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist with serotonin 5-HT1A receptor partial agonist and serotonin 5-HT2A antagonist properties, is approved to treat manic and depressive episodes of bipolar disorder. Post hoc analyses evaluated efficacy across symptoms in bipolar depression. Methods: Pooled data were analyzed from 3 phase 2 or 3, randomized, double-blind, placebo-controlled studies of adults with bipolar disorder and a major depressive episode. Mean change from baseline to week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) total score and individual item scores were analyzed in individual dose groups (1.5 mg/d, 3 mg/d) and overall cariprazine (1.5-3 mg/d). Pooled safety was evaluated via adverse events. Results: A significantly greater difference in mean change from baseline in MADRS total score was seen for each cariprazine dose group versus placebo (least squares mean difference vs placebo: 1.5-3 mg/d = -2.6, 1.5 mg/d = -2.8, 3 mg/d = -2.4) (P < .001 all). Significant differences versus placebo were seen on all individual MADRS items except inner tension for the overall cariprazine group (P < .05). Cariprazine was generally well tolerated. Conclusions: Cariprazine demonstrated broad efficacy across symptoms of depression in bipolar disorder. In previous post hoc analyses, cariprazine also demonstrated broad efficacy across manic symptoms, suggesting that it is effective across the wide range of symptoms on the bipolar spectrum. A 1.5-mg/d starting dose and slow titration resulted in lower rates of some adverse events in the bipolar depression studies versus the mania studies. Trial Registration: ClinicalTrials.gov identifiers: NCT01396447, NCT02670538, NCT02670551.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Neurotransmissores/farmacologia , Piperazinas/farmacologia , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurotransmissores/administração & dosagem , Neurotransmissores/efeitos adversos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Resultado do Tratamento
4.
Proc Natl Acad Sci U S A ; 117(21): 11781-11787, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32385158

RESUMO

Benzodiazepines (BZDs) represent the gold standard of anxiolytic pharmacotherapy; however, their clinical benefit is limited by side effects and addictive potential. Consequently, there is an urgent need to develop novel and safe anxiolytics. The peptide hormone oxytocin (OXT) exhibits anxiolytic-like properties in animals and humans, but whether OXT and BZDs share similar effects on the neural circuitry of fear is unclear. Therefore, the rationale of this ultra-high-field functional MRI (fMRI) study was to test OXT against the clinical comparator lorazepam (LZP) with regard to their neuromodulatory effects on local and network responses to fear-related stimuli. One hundred twenty-eight healthy male participants volunteered in this randomized double-blind, placebo-controlled, between-group study. Before scanning using an emotional face-matching paradigm, participants were randomly administered a single dose of OXT (24 IU), LZP (1 mg), or placebo. On the behavioral level, LZP, but not OXT, caused mild sedation, as evidenced by a 19% increase in reaction times. On the neural level, both OXT and LZP inhibited responses to fearful faces vs. neutral faces within the centromedial amygdala (cmA). In contrast, they had different effects on intra-amygdalar connectivity; OXT strengthened the coupling between the cmA and basolateral amygdala, whereas LZP increased the interplay between the cmA and superficial amygdala. Furthermore, OXT, but not LZP, enhanced the coupling between the cmA and the precuneus and dorsomedial prefrontal cortex. These data implicate inhibition of the cmA as a common denominator of anxiolytic action, with only OXT inducing large-scale connectivity changes of potential therapeutic relevance.


Assuntos
Tonsila do Cerebelo , Medo/efeitos dos fármacos , Lorazepam/farmacologia , Ocitocina/farmacologia , Adulto , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/fisiologia , Medo/fisiologia , Humanos , Imagem por Ressonância Magnética , Masculino , Neurotransmissores/farmacologia , Adulto Jovem
5.
Proc Natl Acad Sci U S A ; 117(12): 6831-6835, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32152102

RESUMO

Glutamate is the major excitatory neurotransmitter in the brain, and photochemical release of glutamate (or uncaging) is a chemical technique widely used by biologists to interrogate its physiology. A basic prerequisite of these optical probes is bio-inertness before photolysis. However, all caged glutamates are known to have strong antagonism toward receptors of γ-aminobutyric acid, the major inhibitory transmitter. We have developed a caged glutamate probe that is inert toward these receptors at concentrations that are effective for photolysis with violet light. Pharmacological tests in vitro revealed that attachment of a fifth-generation (G5) dendrimer (i.e., cloaking) to the widely used 4-methoxy-7-nitro-indolinyl(MNI)-Glu probe prevented such off-target effects while not changing the photochemical properties of MNI-Glu significantly. G5-MNI-Glu was used with optofluidic delivery to stimulate dopamine neurons of the ventral tegmental area of freely moving mice in a conditioned place-preference protocol so as to mediate Pavlovian conditioning.


Assuntos
Glutamatos/farmacologia , Indóis/farmacologia , Aprendizagem/fisiologia , Microfluídica , Neurônios/fisiologia , Neurotransmissores/farmacologia , Animais , Aprendizagem/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Neuroquímica , Neurônios/efeitos dos fármacos , Fotoquímica , Fotólise , Receptores de GABA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
6.
Nat Rev Gastroenterol Hepatol ; 17(3): 184-192, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32071420

RESUMO

Gut-brain dysregulation has been recognized by the scientific community as being crucial to the understanding of chronic gastrointestinal conditions, and this has translated into the practice of a newly established discipline, psychogastroenterology. Along with psychotherapy, antidepressants (a subtype of central neuromodulators) have been proposed as treatments for gut-brain disorders that might benefit both psychological and gastrointestinal health. Antidepressants have been found to be effective for the treatment of comorbid anxiety and depression, pain and impaired sleep. Although the efficacy of antidepressants is well established in disorders of gut-brain interaction (DGBI), evidence is only now emerging in IBD. This Perspective discusses the use of antidepressants in DGBI and IBD, focusing on how what we have learnt about the role of antidepressants in DGBI could be applied to help optimize the management of IBD.


Assuntos
Antidepressivos/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Antidepressivos/efeitos adversos , Antidepressivos/farmacologia , Encéfalo/fisiopatologia , Dor Crônica/tratamento farmacológico , Comorbidade , Humanos , Doenças Inflamatórias Intestinais/fisiopatologia , Doenças Inflamatórias Intestinais/psicologia , Neurotransmissores/farmacologia , Neurotransmissores/uso terapêutico , Medição de Risco/métodos , Transtornos do Sono-Vigília/tratamento farmacológico
7.
Biochemistry (Mosc) ; 85(Suppl 1): S108-S130, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32087056

RESUMO

It had been commonly believed for a long time, that once established, degeneration of the central nervous system (CNS) is irreparable, and that adult person merely cannot restore dead or injured neurons. The existence of stem cells (SCs) in the mature brain, an organ with minimal regenerative ability, had been ignored for many years. Currently accepted that specific structures of the adult brain contain neural SCs (NSCs) that can self-renew and generate terminally differentiated brain cells, including neurons and glia. However, their contribution to the regulation of brain activity and brain regeneration in natural aging and pathology is still a subject of ongoing studies. Since the 1970s, when Fuad Lechin suggested the existence of repair mechanisms in the brain, new exhilarating data from scientists around the world have expanded our knowledge on the mechanisms implicated in the generation of various cell phenotypes supporting the brain, regulation of brain activity by these newly generated cells, and participation of SCs in brain homeostasis and regeneration. The prospects of the SC research are truthfully infinite and hitherto challenging to forecast. Once researchers resolve the issues regarding SC expansion and maintenance, the implementation of the SC-based platform could help to treat tissues and organs impaired or damaged in many devastating human diseases. Over the past 10 years, the number of studies on SCs has increased exponentially, and we have already become witnesses of crucial discoveries in SC biology. Comprehension of the mechanisms of neurogenesis regulation is essential for the development of new therapeutic approaches for currently incurable neurodegenerative diseases and neuroblastomas. In this review, we present the latest achievements in this fast-moving field and discuss essential aspects of NSC biology, including SC regulation by hormones, neurotransmitters, and transcription factors, along with the achievements of genetic and chemical reprogramming for the safe use of SCs in vitro and in vivo.


Assuntos
Envelhecimento/metabolismo , Regeneração Nervosa/fisiologia , Células-Tronco Neurais/metabolismo , Doenças Neurodegenerativas/terapia , Adulto , Animais , Transplante de Células/efeitos adversos , Transplante de Células/métodos , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Epigênese Genética , Hormônios/metabolismo , Hormônios/farmacologia , Humanos , Células-Tronco Pluripotentes Induzidas/transplante , Doenças Neurodegenerativas/metabolismo , Neurogênese , Neurotransmissores/metabolismo , Neurotransmissores/farmacologia , Fatores de Transcrição/metabolismo
8.
Eur J Pharmacol ; 870: 172824, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-31778672

RESUMO

Post-traumatic stress disorder (PTSD) is a psychopathological response that develops after exposure to an extreme life-threatening traumatic event. Its prevalence ranges from 0.5% to 14.5% worldwide. Due to the complex pathophysiology of PTSD, currently available treatment approaches are associated with high chances of failure, thus further research to identify better pharmacotherapeutic approaches is needed. The traumatic event associated with fear memories plays an important role in the development of PTSD and could be considered as the main culprit. PTSD patient feels frightened in a safe environment as the memories of the traumatic event are revisited. Neurocircuit involving normal processing of fear memories get disturbed in PTSD hence making a fear memory to remain to dominate even after years of trauma. Persistence of fear memories could be explained by acquisition, re-(consolidation) and extinction triad as all of these processes have been widely explored in preclinical as well as clinical studies and set a therapeutic platform for fear memory associated disorders. This review focuses on neurocircuit and pathophysiology of PTSD in context to fear memories and pharmacological targeting of fear memory for the management of PTSD.


Assuntos
Medo/psicologia , Neurotransmissores/farmacologia , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/psicologia , Animais , Extinção Psicológica , Ácido Glutâmico/metabolismo , Humanos , Consolidação da Memória , Receptores de N-Metil-D-Aspartato/metabolismo , Fatores de Risco , Transdução de Sinais , Resultado do Tratamento
9.
Biochim Biophys Acta Biomembr ; 1862(2): 183099, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31697903

RESUMO

Despite decades of intense research to understand the phenomenon of anesthesia and its membrane-related changes in neural transmission, where lipids and proteins have been proposed as primary targets of anesthetics, the involved action mechanisms remain unclear. Based on the overall agreement that anesthetics and neurotransmitters induce particular modifications in the plasma membrane of neurons, triggering specific responses and changes in their energetic states, we present here a thermal study to investigate membrane effects in a lipid-protein model made of 1,2-dimyristoyl-sn-glycero-3-phosphocholine and albumin from chicken egg white under the influence of neurotransmitters and anesthetics. First, we observe how ovalbumin, ovotransferrin, and lysozyme (main albumin constituents from chicken egg white) interact with the lipid membrane enhancing their lipophilic character while exposing their hydrophobic domains. This produces a lipid separation and a more ordered hybrid lipid-protein assembly. Second, we measured the thermotropic changes of this assembly induced by acetylcholine, γ-aminobutiric acid, tetracaine, and pentobarbital. Although the protein in our study is not a receptor, our results are striking, for they give evidence of the great importance of non-specific interactions in the anesthesia mechanism.


Assuntos
Anestésicos/farmacologia , Membranas Artificiais , Modelos Biológicos , Neurotransmissores/farmacologia , Temperatura , Albuminas , Animais , Galinhas , Dimiristoilfosfatidilcolina , Proteínas do Ovo , Interações Hidrofóbicas e Hidrofílicas , Lipídeos de Membrana , Proteínas de Membrana
10.
Toxicol Lett ; 321: 21-31, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31830555

RESUMO

Nerve agents inhibit acetylcholinesterase (AChE), leading to a build-up of acetylcholine (ACh) and overstimulation at cholinergic synapses. Current post-exposure nerve agent treatment includes atropine to treat overstimulation at muscarinic synapses, a benzodiazepine anti-convulsant, and an oxime to restore the function of AChE. Aside from the oxime, the components do not act directly to reduce the overstimulation at nicotinic synapses. The false transmitters acetylmonoethylcholine (AMECh) and acetyldiethylcholine (ADECh) are analogs of ACh, synthesised similarly at synapses. AMECh and ADECh are partial agonists, with reduced activity compared to ACh, so it was hypothesised the false transmitters could reduce overstimulation. Synthetic routes to AMECh and ADECh, and their precursors, monoethylcholine (MECh) and diethylcholine (DECh), were devised, allowing them to be produced easily on a laboratory-scale. The mechanism of action of the false transmitters was investigated in vitro. AMECh acted as a partial agonist at human muscarinic (M1 and M3) and muscle-type nicotinic receptors, and ADECh was a partial agonist only at certain muscarinic subtypes. Their precursors acted as antagonists at muscle-type nicotinic, but not muscarinic receptors. Administration of MECh and DECh improved neuromuscular function in the soman-exposed guinea-pig hemi-diaphragm preparation. False transmitters may therefore help reduce nerve agent induced overstimulation at cholinergic synapses.


Assuntos
Acetilcolina/análogos & derivados , Antídotos/farmacologia , Colina/análogos & derivados , Inibidores da Colinesterase/envenenamento , Diafragma/inervação , Agentes Neurotóxicos/envenenamento , Neurotransmissores/farmacologia , Intoxicação por Organofosfatos/tratamento farmacológico , Soman/envenenamento , Sinapses/efeitos dos fármacos , Acetilcolina/síntese química , Acetilcolina/metabolismo , Acetilcolina/farmacologia , Acetilcolinesterase/metabolismo , Animais , Antídotos/síntese química , Células CHO , Linhagem Celular Tumoral , Colina/síntese química , Colina/farmacologia , Cricetulus , Agonismo Parcial de Drogas , Cobaias , Humanos , Masculino , Neurotransmissores/síntese química , Intoxicação por Organofosfatos/enzimologia , Intoxicação por Organofosfatos/fisiopatologia , Receptores Colinérgicos/efeitos dos fármacos , Receptores Colinérgicos/genética , Receptores Colinérgicos/metabolismo , Sinapses/enzimologia
11.
Biol Aujourdhui ; 213(3-4): 141-145, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31829934

RESUMO

Addiction is a chronic disease that has serious consequences, both in terms of public health and economy. Clear characteristics distinguish recreational and controlled use from addiction. Thus, today, addiction includes the notions of compulsive drug use, associated with a loss of control over consumption, leading to craving. When consumption is stopped, withdrawal symptoms may emerge: a negative emotional state, cognitive problems and physical symptoms with some products (alcohol and opiates, for example). Relapse episodes may occur during this withdrawal period, countering the negative effects of withdrawal. Relapse episodes can also be observed after long periods of abstinence. They can be precipitated by re-exposure to the context in which the drugs were taken, or by stress. Regardless of the stage of addiction (e.g., development of the addictive behavior, or relapse) changes in brain function and structure can be observed. Some brain structures are therefore modified, such as the prefrontal cortex, where several neuroadaptations have been identified. Some of these changes are described in this paper.


Assuntos
Cocaína/farmacologia , Rede Nervosa/efeitos dos fármacos , Neurotransmissores/farmacologia , Psicotrópicos/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Animais , Comportamento Aditivo/induzido quimicamente , Comportamento Aditivo/fisiopatologia , Comportamento Aditivo/psicologia , Transtornos Relacionados ao Uso de Cocaína/etiologia , Transtornos Relacionados ao Uso de Cocaína/fisiopatologia , Transtornos Relacionados ao Uso de Cocaína/psicologia , Humanos , Rede Nervosa/fisiologia , Transdução de Sinais/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/fisiopatologia , Síndrome de Abstinência a Substâncias/psicologia
12.
Biomed Res Int ; 2019: 1767203, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31815123

RESUMO

Neurological diseases particularly Alzheimer's disease (AD), Parkinson's disease (PD), stroke, and epilepsy are on the rise all around the world causing morbidity and mortality globally with a common symptom of gradual loss or impairment of motor behaviour. Striatum, which is a component of the basal ganglia, is involved in facilitating voluntary movement while the cerebellum is involved in the maintenance of balance and coordination of voluntary movements. Dopamine, serotonin, gamma-aminobutyric acid (GABA), and glutamate, to name a few, interact in regulating the excitation and inhibition of motor neurons. In another hand, interestingly, the motor loss associated with neurological diseases is possibly resulted from neuroinflammation induced by the neuroimmune system. Toll-like receptors (TLRs) are present in the central nervous system (CNS), specifically and primarily expressed in microglia and are also found on neurons and astrocytes, functioning mainly in the regulation of proinflammatory cytokine production. TLRs are always found to be associated or involved in the induction of neuroinflammation in neurodegenerative diseases. Activation of toll-like receptor 4 (TLR4) through TLR4 agonist, lipopolysaccharide (LPS), stimulation initiate a signaling cascade whereby the TLR4-LPS interaction has been found to result in physiological and behavioural changes including retardation of motor activity in the mouse model. TLR4 inhibitor TAK-242 was reflected in the reduction of the spinal cord pathology along with the motor improvement in ALS mouse. There is cross talk with neuroinflammation and neurochemicals. For example, TLR4 activation by LPS is noted to release proinflammatory cytokines, IL-1ß, from microglia that subsequently suppresses GABA receptor activities at the postsynaptic site and reduces GABA synthesis at the presynaptic site. Glial glutamate transporter activities are also found to be suppressed, showing the association between TLR4 activation and the related neurotransmitters and corresponding receptors and transporters in the event of neuroinflammation. This review is helpful to understand the connection between neurotransmitter and neuroinflammation in striatum- and cerebellum-mediated motor behaviour.


Assuntos
Cerebelo/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Inflamação , Neurônios Motores/efeitos dos fármacos , Neurotransmissores/farmacologia , Animais , Astrócitos/metabolismo , Sistema Nervoso Central/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Dopamina/farmacologia , Ácido Glutâmico/farmacologia , Humanos , Interleucina-1beta , Lipopolissacarídeos/efeitos adversos , Camundongos , Microglia/metabolismo , Serotonina/farmacologia , Receptor 4 Toll-Like , Receptores Toll-Like , Ácido gama-Aminobutírico/farmacologia
13.
Bull Exp Biol Med ; 168(2): 193-198, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31776959

RESUMO

Stimulation of the serotoninergic system (5-hydroxytryptophan, 50 mg/kg; fluoxetine, 3 mg/kg) induced a significant increase in HR and a reduction in the amplitude of all waves of the heart rhythm variability. Stimulation of the dopaminergic system (L-DOPA and amantadine, 20 mg/kg each) resulted in a moderate increase in HR and amplitudes of low-frequency (LF) and very-low-frequency (VLF) waves of the heart rhythm variability. Successive blockade of nicotinic (hexamethonium, 7 mg/kg) and muscarinic cholinergic receptors (atropine, 1 mg/kg) leads to a significant decrease in the variability of cardiointervals (almost to complete levelling) both under control conditions and after stimulation of the neurotransmitter systems. Serotonin receptor blockade (promethazine, 2 mg/kg) did not affect HR, but reduced the amplitude of LF- and VLF-waves. Under conditions of serotoninergic system stimulation, the blockade of serotonin receptors was followed by a significant HR acceleration without changes in heart rhythm variability; blockade of dopamine receptors (sulpiride, 1 mg/kg) induced HR acceleration and increase in the amplitude of LF- and VLF-waves; blockade of dopamine receptors under conditions of dopamine system stimulation was followed by a significant increase in HR and a decrease in the amplitude of all waves of the heart rhythm variability. It can be hypothesized that serotonin- and dopaminergic systems affect the heart rhythm via cardiomyocyte receptors and via modulation of activity of the adrenergic and cholinergic systems. The effects of serotonin- and dopaminergic systems can be considered as synergic in the CNS, and antagonistic at the periphery.


Assuntos
Neurônios Dopaminérgicos/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Neurotransmissores/farmacologia , Receptores de Neurotransmissores/efeitos dos fármacos , Neurônios Serotoninérgicos/fisiologia , Animais , Colina/antagonistas & inibidores , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Masculino , Agonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/farmacologia , Ratos , Receptores Dopaminérgicos/metabolismo , Receptores Muscarínicos/metabolismo , Receptores de Serotonina/metabolismo , Neurônios Serotoninérgicos/efeitos dos fármacos , Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia
14.
J Pept Sci ; 25(12): e3224, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31743956

RESUMO

The gastrin-releasing peptide receptor (GRPR) is part of the bombesin receptor family and a well-known target in cancer diagnosis and therapy. In the last decade, promising results have been achieved by using peptide-drug conjugates, which allow selective targeting of GRPR expressing tumor cells. Most ligands, however, have been antagonists even though agonists can lead to higher tumor uptake owing to their internalization. So far, only a few studies focused on the identification of small GRPR-selective agonists that are metabolically stable. Here, we developed novel bombesin analogs with high selectivity for the GRPR and improved blood plasma stability. The most promising analog [d-Phe6 , ß-Ala11 , NMe-Ala13 , Nle14 ]Bn(6-14) displays an activity of 0.3nM at the GRPR, a more than 4000-fold selectivity over the other two bombesin receptors and more than 75% stability in human blood plasma after 24 hours. This analog is proposed as a promising drug shuttle for the intracellular delivery of different payloads in targeted tumor therapy approaches.


Assuntos
Bombesina/farmacologia , Neurotransmissores/farmacologia , Receptores da Bombesina/agonistas , Bombesina/análogos & derivados , Bombesina/sangue , Células Cultivadas , Estabilidade de Medicamentos , Humanos , Neurotransmissores/sangue , Neurotransmissores/química
15.
Sci Rep ; 9(1): 17086, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31745219

RESUMO

Gastrin-releasing peptide receptors (GRPRs) are promising targets in oligometastatic prostate cancer. We have recently used 55Co (T1/2 = 17.5 h) as a label for next day PET imaging of GRPR expression obtaining high imaging contrast. The radionuclide-chelator combination can significantly influence the biodistribution of radiopeptides. Therefore, in this study, we hypothesized that the properties of 55Co-labeled PEG2-RM26 can be improved by identifying the optimal macrocyclic chelator. All analogues (X-PEG2-RM26, X = NOTA,NODAGA,DOTA,DOTAGA) were successfully labeled with radiocobalt with high yields and demonstrated high stability. The radiopeptides bound specifically and with picomolar affinity to GRPR and their cellular processing was characterized by low internalization. The best binding capacity was found for DOTA-PEG2-RM26. Ex vivo biodistribution in PC-3 xenografted mice was characterized by rapid blood clearance via renal excretion. Tumor uptake was similar for all conjugates at 3 h pi, exceeding the uptake in all other organs. Higher kidney uptake and longer retention were associated with N-terminal negative charge (DOTAGA-containing conjugate). Tumor-to-organ ratios increased over time for all constructs, although significant chelator-dependent differences were observed. Concordant with affinity measurements, DOTA-analog had the best retention of activity in tumors, resulting in the highest tumor-to-blood ratio 24 h pi, which translated into high contrast PET/CT imaging (using 55Co).


Assuntos
Bombesina/farmacocinética , Radioisótopos de Cobalto/farmacocinética , Compostos Macrocíclicos/química , Compostos Organometálicos/química , Tomografia por Emissão de Pósitrons/métodos , Neoplasias da Próstata/patologia , Receptores da Bombesina/antagonistas & inibidores , Animais , Apoptose , Bombesina/análogos & derivados , Bombesina/farmacologia , Proliferação de Células , Quelantes/química , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Neurotransmissores/química , Neurotransmissores/farmacocinética , Neurotransmissores/farmacologia , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Phys Chem Chem Phys ; 21(41): 22700-22703, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31579899

RESUMO

We use cold ion spectroscopy and quantum-chemical computations to solve the structures of opioid peptides enkephalins in the gas phase. The derived structural parameters clearly correlate with the known pharmacological efficiency of the studied drugs, suggesting that gas-phase methods, perhaps, can be used for predicting the relative potency of ligand drugs that target the hydrophobic pockets of receptors.


Assuntos
Encefalinas/química , Gases/química , Modelos Moleculares , Análise Espectral , Encefalinas/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Neurotransmissores/química , Neurotransmissores/farmacologia , Relação Estrutura-Atividade
17.
Brain Behav ; 9(12): e01428, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31571393

RESUMO

INTRODUCTION: Rodent primary sensory neurons are commonly used for studying itch and pain neurophysiology, but translation from rodents to larger mammals and humans is not direct and requires further validation to make correlations. METHODS: This study developed a primary canine sensory neuron culture from dorsal root ganglia (DRG) excised from cadaver dogs. Additionally, the canine DRG cell cultures developed were used for single-cell ratiometric calcium imaging, with the activation of neurons to the following pruritogenic and algogenic substances: histamine, chloroquine, canine protease-activated receptor 2 (PAR2) activating peptide (SLIGKT), compound 48/80, 5-hydroxytryptamine receptor agonist (5-HT), bovine adrenal medulla peptide (BAM8-22), substance P, allyl isothiocyanate (AITC), and capsaicin. RESULTS: This study demonstrates a simple dissection and rapid processing of DRG collected from canine cadavers used to create viable primary sensory neuron cultures to measure responses to pruritogens and algogens. CONCLUSION: Ratiometric calcium imaging demonstrated that small-diameter canine sensory neurons can be activated by multiple stimuli, and a single neuron can react to both a pruritogenic stimulation and an algogenic stimulation.


Assuntos
Imagem Molecular/métodos , Prurido/fisiopatologia , Células Receptoras Sensoriais/fisiologia , Animais , Cadáver , Radioisótopos de Cálcio , Capsaicina/farmacologia , Bovinos , Células Cultivadas , Cloroquina/farmacologia , Cães , Gânglios Espinais/fisiopatologia , Histamina/farmacologia , Humanos , Laminectomia , Neurotransmissores/farmacologia , Dor/fisiopatologia , Fragmentos de Peptídeos/farmacologia , Prurido/induzido quimicamente , Compostos Radiofarmacêuticos , Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Substância P/farmacologia
18.
Adv Immunol ; 143: 1-9, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31607366

RESUMO

Diverse infectious, inflammatory, and environmental stimuli induce type 2 inflammation in the body. Group 2 innate lymphoid cells (ILC2s) are potent producers of type 2 cytokines and play important roles in promoting type 2 inflammation. In addition to alarmins and other cytokines which are known to regulate ILC2 responses, emerging studies identified the regulation of ILC2s by the nervous system through neurotransmitter and neuropeptides. In this review, we highlight recent advances in the regulation of ILC2s and type 2 inflammation by the nervous system.


Assuntos
Citocinas/metabolismo , Imunidade Inata , Inflamação/imunologia , Linfócitos/imunologia , Neuroimunomodulação , Neurônios/imunologia , Neuropeptídeos/metabolismo , Animais , Células Endócrinas/imunologia , Células Endócrinas/metabolismo , Retroalimentação Fisiológica/fisiologia , Humanos , Linfócitos/metabolismo , Linfócitos/fisiologia , Neurônios/metabolismo , Neurotransmissores/imunologia , Neurotransmissores/metabolismo , Neurotransmissores/farmacologia , Células Estromais/metabolismo , Células Estromais/fisiologia
19.
Eur J Pharmacol ; 864: 172713, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31586631

RESUMO

The role of mast cells during inflammatory bowel diseases (IBD) is discussed controversially. Whereas several studies report an increase in mast cell density during IBD, others found a decrease. Recently, we observed a reduced response to mast cell degranulation induced by antigen contact in a colitis model. As the effects of mast cell mediators on epithelial ion transport are mediated indirectly via stimulation of secretomotor neurons, we investigated in vitro whether proinflammatory cytokines change the response to mast cell degranulation. Tumor necrosis factor α (TNFα) and a mix of proinflammatory cytokines caused an increase of short-circuit current (Isc) and tissue conductance in rat colon. Anion secretion induced by histamine was downregulated in the presence of interleukin-1ß (IL-1ß) and the cytokine mix, whereas the response to the mast cell stimulator compound 48/80 was not changed significantly. In a coculture of rat submucosal ganglionic cells with a mast cell line (RBL-2H3), TNFα preincubation for 1 d increased the percentage of neurons responding to mast cell degranulation with an increase of the cytosolic Ca2+ concentration and enhanced the amplitude of this response. Consequently, the downregulation of epithelial secretion is compensated by an increased sensitivity of secretomotor neurons leading to a constant response of the epithelium to compound 48/80. Furthermore, enteric neurons can modify mast cell functions as nicotine inhibited the increase in cytosolic Ca2+ concentration of RBL-2H3 cells and the Isc evoked by compound 48/80. Consequently, these in vitro models deliver new insights into cellular interactions in the gut wall under inflammatory conditions.


Assuntos
Comunicação Celular/efeitos dos fármacos , Citocinas/farmacologia , Mucosa Intestinal/citologia , Mastócitos/citologia , Neurônios/citologia , Neurotransmissores/farmacologia , Animais , Cálcio/metabolismo , Citosol/efeitos dos fármacos , Citosol/metabolismo , Feminino , Mucosa Intestinal/metabolismo , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Permeabilidade/efeitos dos fármacos , Ratos , Ratos Wistar , p-Metoxi-N-metilfenetilamina/farmacologia
20.
J Clin Psychopharmacol ; 39(6): 597-603, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31652166

RESUMO

BACKGROUND: Managing agitation and hostility represents a significant treatment challenge in schizophrenia. The aim of this analysis was to evaluate the short- and long-term efficacy of brexpiprazole for reducing agitation and hostility in schizophrenia. METHODS: This was a post hoc analysis of data from two 6-week, randomized, double-blind, placebo-controlled studies (ClinicalTrials.gov identifiers, NCT01396421 and NCT01393613) and a 52-week, open-label, extension study (NCT01397786). In the short-term studies, 1094 patients received placebo, 2 mg/d of brexpiprazole, or 4 mg/d of brexpiprazole; 346 brexpiprazole-treated patients rolled over into the long-term study and received 1 to 4 mg/d of brexpiprazole. Agitation was assessed using the Positive and Negative Syndrome Scale (PANSS) Excited Component (EC), and hostility was assessed using the PANSS hostility item (P7). RESULTS: Brexpiprazole improved PANSS-EC score over 6 weeks, with least squares mean differences versus placebo of -0.69 (95% confidence limits, -1.28, -0.11) for 2 mg/d (P = 0.020) and -1.11 (-1.70, -0.53) for 4 mg/d (P = 0.0002). In the subgroup with hostility at baseline (P7 score ≥3; 50.8% of the randomized sample), least squares mean differences versus placebo at week 6 on the PANSS-EC were -0.63 (-1.54, 0.28) for 2 mg/d (P = 0.18) and -1.03 (-1.92, -0.14) for 4 mg/d (P = 0.024), and on P7 (adjusted for positive symptoms) were -0.27 (-0.53, -0.01) for 2 mg/d (P = 0.038) and -0.34 (-0.59, -0.09) for 4 mg/d (P = 0.0080). The improvements were maintained over 58 weeks. Adverse events were generally comparable between treatment groups over 6 weeks; the incidence of akathisia among patients with hostility was 5.9% with placebo, 5.2% with 2 mg/d, and 8.6% with 4 mg/d. CONCLUSIONS: Brexpiprazole has the potential to be an efficacious and well-tolerated treatment for agitation and hostility among patients with schizophrenia.


Assuntos
Hostilidade , Neurotransmissores/farmacologia , Avaliação de Resultados em Cuidados de Saúde , Agitação Psicomotora/tratamento farmacológico , Quinolonas/farmacologia , Esquizofrenia/tratamento farmacológico , Tiofenos/farmacologia , Adolescente , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurotransmissores/administração & dosagem , Quinolonas/administração & dosagem , Esquizofrenia/complicações , Esquizofrenia/fisiopatologia , Índice de Gravidade de Doença , Tiofenos/administração & dosagem , Adulto Jovem
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