RESUMO
Type 1 diabetes (T1D) is a complex metabolic autoimmune disorder that affects millions of individuals worldwide and often leads to significant comorbidities. However, the precise trigger of autoimmunity and disease onset remain incompletely elucidated. This integrative perspective article synthesizes the cumulative role of gene-environment interaction in the pathophysiology of T1D. Genetics plays a significant role in T1D susceptibility, particularly at the major histocompatibility complex (MHC) locus and cathepsin H (CTSH) locus. In addition to genetics, environmental factors such as viral infections, pesticide exposure, and changes in the gut microbiome have been associated with the development of T1D. Alterations in the gut microbiome impact mucosal integrity and immune tolerance, increasing gut permeability through molecular mimicry and modulation of the gut immune system, thereby increasing the risk of T1D potentially through the induction of autoimmunity. HLA class II haplotypes with known effects on T1D incidence may directly correlate to changes in the gut microbiome, but precisely how the genes influence changes in the gut microbiome, and how these changes provoke T1D, requires further investigations. These gene-environment interactions are hypothesized to increase susceptibility to T1D through epigenetic changes such as DNA methylation and histone modification, which in turn modify gene expression. There is a need to determine the efficacy of new interventions that target these epigenetic modifications such as "epidrugs", which will provide novel avenues for the effective management of T1D leading to improved quality of life of affected individuals and their families/caregivers.
Assuntos
Diabetes Mellitus Tipo 1 , Interação Gene-Ambiente , Humanos , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/epidemiologia , Qualidade de Vida , Suscetibilidade a Doenças , Epigênese GenéticaRESUMO
Blood glucose monitoring constitutes a pivotal element in the clinical management of Type 1 diabetes (T1D), a globally escalating metabolic disorder. Continuous glucose monitoring (CGM) devices have demonstrated efficacy in optimizing glycemic control, mitigating adverse health outcomes, and augmenting the overall quality of life for individuals afflicted with T1D. Recent progress in the field encompasses the refinement of electrochemical sensors, which enhances the effectiveness of blood glucose monitoring. This progress empowers patients to assume greater control over their health, alleviating the burdens associated with their condition, and contributing to the overall alleviation of the healthcare system. The introduction of novel medical devices, whether derived from existing prototypes or originating as innovative creations, necessitates adherence to a rigorous approval process regulated by the Food and Drug Administration (FDA). Diverse device classifications, stratified by their associated risks, dictate distinct approval pathways, each characterized by varying timelines. This review underscores recent advancements in blood glucose monitoring devices primarily based on electrochemical sensors and elucidates their regulatory journey towards FDA approval. The advent of innovative, non-invasive blood glucose monitoring devices holds promise for maintaining stringent glycemic control, thereby preventing T1D-associated comorbidities, and extending the life expectancy of affected individuals.
Assuntos
Diabetes Mellitus Tipo 1 , Estados Unidos/epidemiologia , Humanos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Glicemia , Automonitorização da Glicemia , Qualidade de Vida , United States Food and Drug AdministrationRESUMO
OBJECTIVES: The aim of this systematic review article is to evaluate the relationship between diabetes mellitus (DM) and sensorineural hearing loss (SNHL) utilizing preclinical animal models. The review focused on studies assessing SNHL in diabetic animal models, elucidating the mechanisms of DM-associated SNHL, and exploring the response of diabetic animal models to noise overexposure. We also discussed studies investigating the efficacy of potential therapeutic strategies for amelioration of DM-associated SNHL in the animal models. METHODS: A protocol of this systematic review was designed a priori and was registered in the PROSPERO database (registration number: CRD42023439961). We conducted a comprehensive search on PubMed, Science Direct, Web of Science, Scopus, and EMBASE databases. A minimum of three reviewers independently screened, selected, and extracted data. The risk of bias assessment of eligible studies was conducted using the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) tool. RESULTS: Following the screening of 238 studies, twelve original articles were included in this systematic review. The studies revealed that hyperglycemia significantly affects auditory function, with various pathological mechanisms contributing to DM-induced hearing impairment, including cochlear synaptopathy, microangiopathy, neuropathy, oxidative stress, mitochondrial abnormalities, and apoptosis-mediated cell death. Emerging interventions, such as Asiaticoside, Trigonelline, Chlorogenic acid, and Huotanquyu granules, demonstrated efficacy in providing otoprotection for preserving cochlear hair cells and hearing function. CONCLUSIONS: Our systematic review delves into the intricate relationship between DM and hearing impairment in animal models. Future research should focus on targeted therapies to enhance cochlear mitochondrial function, alleviate oxidative stress, and regulate apoptosis. The association between SNHL and social isolation as well as cognitive decline underscores the necessity for innovative therapeutic modalities addressing yet undiscovered mechanisms. Translating findings from animal models to human studies will validate these findings, offering a synergistic approach to effectively manage DM-associated co-morbidities such as hearing impairment.
Assuntos
Modelos Animais de Doenças , Animais , Perda Auditiva Neurossensorial , Humanos , Estresse Oxidativo/efeitos dos fármacos , Diabetes Mellitus , Diabetes Mellitus Experimental/complicações , Perda AuditivaRESUMO
Diabetic Peripheral Neuropathy (DPN) is a prevalent and debilitating complication of diabetes, affecting a significant proportion of the diabetic population. Neuromodulation, an emerging therapeutic approach, has shown promise in the management of DPN symptoms. This systematic review aims to synthesize and analyze the current advancements in neuromodulation techniques for the treatment of DPN utilizing studies with preclinical animal models. A comprehensive search was conducted across multiple databases, including PubMed, Scopus, and Web of Science. Inclusion criteria were focused on studies utilizing preclinical animal models for DPN that investigated the efficacy of various neuromodulation techniques, such as spinal cord stimulation, transcranial magnetic stimulation, and peripheral nerve stimulation. The findings suggest that neuromodulation significantly alleviated pain symptoms associated with DPN. Moreover, some studies reported improvements in nerve conduction velocity and reduction in nerve damage. The mechanisms underlying these effects appeared to involve modulation of pain pathways and enhancement of neurotrophic factors. However, the review also highlights the variability in methodology and stimulation parameters across studies, highlighting the need for standardization in future research. Additionally, while the results are promising, the translation of these findings from animal models to human clinical practice requires careful consideration. This review concludes that neuromodulation presents a potentially effective therapeutic strategy for DPN, but further research is necessary to optimize protocols and understand the underlying molecular mechanisms. It also emphasizes the importance of bridging the gap between preclinical findings and clinical applications to improve the management of DPN in diabetic patients.
Assuntos
Neuropatias Diabéticas , Modelos Animais de Doenças , Pesquisa Translacional Biomédica , Animais , Neuropatias Diabéticas/terapia , Neuropatias Diabéticas/fisiopatologia , Humanos , Estimulação da Medula Espinal/métodos , Estimulação Magnética Transcraniana/métodosRESUMO
OBJECTIVES: Type 1 diabetes (T1D) has been associated with several comorbidities such as ocular, renal, and cardiovascular complications. However, the effect of T1D on the auditory system and sensorineural hearing loss (SNHL) is still not clear. The aim of this study was to conduct a systematic review to evaluate whether T1D is associated with hearing impairment. METHODS: The databases PubMed, Science Direct, Scopus, and EMBASE were searched in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Three reviewers independently screened, selected, and extracted data. The Joanna Briggs Institute (JBI) Critical Appraisal Tools for Analytical cross-sectional and case-control studies were used to perform quality assessment and risk of bias analysis on eligible studies. RESULTS: After screening a total of 463 studies, 11 eligible original articles were included in the review to analyze the effects of T1D on the auditory system. The included studies comprised cross-sectional and case-control investigations. A total of 5,792 patients were evaluated across the 11 articles included. The majority of the studies showed that T1D was associated with hearing impairment compared to controls, including differences in PTAs and OAEs, increased mean hearing thresholds, altered acoustic reflex thresholds, and problems with the medial olivocochlear (MOC) reflex inhibitory effect. Significant risk factors included older age, increased disease duration, and higher HbA1C levels. CONCLUSIONS: This systematic review suggests that there is a correlation between T1D and impairment on the auditory system. A multidisciplinary collaboration between endocrinologists, otolaryngologists, and audiologists will lead to early detection of hearing impairment in people with T1D resulting in early intervention and better clinical outcomes in pursuit of improving the quality of life of affected individuals. REGISTRATION: This systematic review is registered in PROSPERO (CRD42023438576).
Assuntos
Diabetes Mellitus Tipo 1 , Perda Auditiva Neurossensorial , Humanos , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Neurossensorial/etiologia , Diabetes Mellitus Tipo 1/complicações , Estudos TransversaisRESUMO
Type 1 diabetes (T1D) is caused by an autoimmune process which culminates in the destruction of insulin-producing beta cells in the pancreas. It is widely believed that a complex and multifactorial interplay between genetic and environmental factors, such as viruses, play a crucial role in the development of the disease. Research over the past few decades has shown that there is not one single viral culprit, nor one single genetic pathway, causing the disease. Rather, viral infections, most notably enteroviruses (EV), appear to accelerate the autoimmune process leading to T1D and are often seen as a precipitator of clinical diagnosis. In support of this hypothesis, the use of anti-viral drugs has recently shown efficacy in preserving beta cell function after onset of diabetes. In this review, we will discuss the various pathways that viral infections utilize to accelerate the development of T1D. There are three key mechanisms linking viral infections to beta-cell death: One is modulated by the direct infection of islets by viruses, resulting in their impaired function, another occurs in a more indirect fashion, by modulating the immune system, and the third is caused by heightened stress on the beta-cell by interferon-mediated increase of insulin resistance. The first two aspects are surprisingly difficult to study, in the case of the former, because there are still many questions about how viruses might persist for longer time periods. In the latter, indirect/immune case, viruses might impact immunity as a hit-and-run scenario, meaning that many or all direct viral footprints quickly vanish, while changes imprinted upon the immune system and the anti-islet autoimmune response persist. Given the fact that viruses are often associated with the precipitation of clinical autoimmunity, there are concerns regarding the impact of the recent global coronavirus-2019 (COVID-19) pandemic on the development of autoimmune disease. The long-term effects of COVID-19 infection on T1D will therefore be discussed, including the increased development of new cases of T1D. Understanding the interplay between viral infections and autoimmunity is crucial for advancing our knowledge in this field and developing targeted therapeutic interventions. In this review we will examine the intricate relationship between viral infections and autoimmunity and discuss potential considerations for prevention and treatment strategies.
Assuntos
COVID-19 , Infecções por Coronavirus , Diabetes Mellitus Tipo 1 , Infecções por Enterovirus , Viroses , Humanos , Diabetes Mellitus Tipo 1/genética , Pâncreas , Infecções por Coronavirus/complicações , COVID-19/complicaçõesRESUMO
The dynamic and continuously evolving field of ophthalmology necessitates rigorous regulatory oversight in the United States. This review outlines the multifaceted Food and Drug Administration's (FDA) approval process for ophthalmic products, detailing the classifications, pathways, and regulatory compliance for devices, drugs, biologics, and combination products. Particular emphasis is placed on distinct frameworks for Class I, II, and III devices, as well as regulations for drugs, biologics, and combination products. The organizational structure of the FDA is detailed, with highlights on specific Ophthalmology oversight divisions, historical regulatory evolution, and initiatives such as Patient-Focused Drug Development. An in-depth examination of the regulatory journey, ranging from initial research to post-marketing surveillance, includes practical guidance through stages such as Pre-Investigational New Drug/Pre-Submission consultations, clinical trials, new drug application/biologics license application/premarket approval submissions, and FDA advisory committee interactions. The article underscores the importance of early interactions with the health authorities, interdisciplinary team collaboration, adherence to current standards, and the anticipation of policy changes to ensure patient safety. It concludes with an analysis of 4 key FDA-approved ophthalmic products, including Eylea®, Luxturna®, Alphagan P®, and the Raindrop® Near Vision Inlay, detailing their contributions to ophthalmic care and offering valuable insights into their respective clinical trials, regulatory pathways, and potential implications. These case studies are included to illustrate both successful and failed ophthalmic product launches, thereby highlighting the importance of alignment with regulatory compliance.
Assuntos
Distinções e Prêmios , Produtos Biológicos , Estados Unidos , Humanos , United States Food and Drug Administration , Aprovação de Drogas , Preparações FarmacêuticasRESUMO
Background: Monocarboxylate transporter 8 (MCT8) deficiency is an X-chromosome-linked neurodevelopmental disorder resulting from impaired thyroid hormone transport across the cell membrane. The diagnosis of MCT8 deficiency is typically delayed owing to the late appearance of signs and symptoms as well as the inability of standard biomarkers of neonatal screening to provide early detection. In this study, we report, for the first time, the ability to detect MCT8 deficiency at birth using dried blood spot (DBS) samples. Methods: We retrospectively measured triiodothyronine (T3), thyroxine (T4), and reverse T3 (rT3) levels in DBS samples obtained at 4-5 days of life from 6 infants with genetically confirmed MCT8 deficiency and from 110 controls. The latter consisted of 58 healthy term neonates obtained at the same time, 16 were stored for more than 1 year before measurement to match samples from the MCT8-deficient infants. Ten DBS samples were collected at day 1 of life and 42 samples were from prematurely born neonates. Measurements were carried out in extract from eight millimeters diameter DBS using liquid chromatography-tandem mass spectrometry. Results: Contrary to characteristic iodothyronine abnormalities of MCT8 deficiency during later life, T3 and T4 values were not discriminatory from those of other study groups. In contrast, rT3 was significantly lower. The T3/rT3 ratio was higher in the DBS samples from the MCT8-deficient infants compared with all other groups with no overlap (p < 0.0001). Conclusions: rT3 and T3/rT3 ratio in DBS samples obtained from neonates can serve as biomarkers to detect MCT8 deficiency at birth.
Assuntos
Teste em Amostras de Sangue Seco , Deficiência Intelectual Ligada ao Cromossomo X/diagnóstico , Transportadores de Ácidos Monocarboxílicos/genética , Hipotonia Muscular/diagnóstico , Atrofia Muscular/diagnóstico , Mutação , Triagem Neonatal , Simportadores/genética , Tri-Iodotironina Reversa/sangue , Tri-Iodotironina/sangue , Biomarcadores/sangue , Diagnóstico Precoce , Feminino , Predisposição Genética para Doença , Humanos , Recém-Nascido , Masculino , Deficiência Intelectual Ligada ao Cromossomo X/sangue , Deficiência Intelectual Ligada ao Cromossomo X/genética , Transportadores de Ácidos Monocarboxílicos/sangue , Transportadores de Ácidos Monocarboxílicos/deficiência , Hipotonia Muscular/sangue , Hipotonia Muscular/genética , Atrofia Muscular/sangue , Atrofia Muscular/genética , Fenótipo , Valor Preditivo dos Testes , Estudos Retrospectivos , Simportadores/sangue , Simportadores/deficiênciaRESUMO
Acute respiratory distress syndrome (ARDS) in COVID-19 is associated with high mortality. Mesenchymal stem cells are known to exert immunomodulatory and anti-inflammatory effects and could yield beneficial effects in COVID-19 ARDS. The objective of this study was to determine safety and explore efficacy of umbilical cord mesenchymal stem cell (UC-MSC) infusions in subjects with COVID-19 ARDS. A double-blind, phase 1/2a, randomized, controlled trial was performed. Randomization and stratification by ARDS severity was used to foster balance among groups. All subjects were analyzed under intention to treat design. Twenty-four subjects were randomized 1:1 to either UC-MSC treatment (n = 12) or the control group (n = 12). Subjects in the UC-MSC treatment group received two intravenous infusions (at day 0 and 3) of 100 ± 20 × 106 UC-MSCs; controls received two infusions of vehicle solution. Both groups received best standard of care. Primary endpoint was safety (adverse events [AEs]) within 6 hours; cardiac arrest or death within 24 hours postinfusion). Secondary endpoints included patient survival at 31 days after the first infusion and time to recovery. No difference was observed between groups in infusion-associated AEs. No serious adverse events (SAEs) were observed related to UC-MSC infusions. UC-MSC infusions in COVID-19 ARDS were found to be safe. Inflammatory cytokines were significantly decreased in UC-MSC-treated subjects at day 6. Treatment was associated with significantly improved patient survival (91% vs 42%, P = .015), SAE-free survival (P = .008), and time to recovery (P = .03). UC-MSC infusions are safe and could be beneficial in treating subjects with COVID-19 ARDS.
Assuntos
Anti-Inflamatórios/uso terapêutico , COVID-19/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Citocinas/sangue , Método Duplo-Cego , Feminino , Humanos , Masculino , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Células-Tronco Mesenquimais , Pessoa de Meia-Idade , SARS-CoV-2/efeitos dos fármacos , Índice de Gravidade de Doença , Resultado do Tratamento , Cordão Umbilical/citologiaRESUMO
Etifoxine (6-chloro-2-ethylamino-4-methyl-4-phenyl-4H-3,1-benzoxazine hydrochloride), a nonbenzodiazepine anxiolytic drug, potentiates GABA(A) receptor function perhaps through stimulation of neurosteroid biosynthesis. However, the exact mechanism of etifoxine action is not fully understood. In this study, we have assessed the possible role of GABAergic neurosteroid like allopregnanolone (ALLO) in the anxiolytic-like effect of etifoxine in rats using elevated plus maze test. Selective GABA(A) receptor agonist, muscimol, ALLO or neurosteroidogenic agents like progesterone, metyrapone or mitochondrial diazepam binding inhibitor receptor (MDR) agonist, FGIN 1-27 significantly heightened the etifoxine-induced anxiolysis. On the other hand, GABA(A) receptor antagonist, bicuculline or neurosteroid biosynthesis inhibitors like finasteride, indomethacin, trilostane or PBR antagonist, PK11195 significantly blocked the effect of etifoxine. Bilateral adrenalectomy did not influence anti-anxiety effect of etifoxine thereby ruling out contribution of adrenal steroids. Thus, our results provide behavioral evidence for the role of neurosteroids like ALLO in the anti-anxiety effect of etifoxine.
Assuntos
Ansiolíticos/uso terapêutico , Ansiedade/tratamento farmacológico , Oxazinas/uso terapêutico , Pregnanolona/fisiologia , Adrenalectomia/métodos , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Bicuculina/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Vias de Administração de Medicamentos , Interações Medicamentosas , Inibidores Enzimáticos/administração & dosagem , Agonistas GABAérgicos/administração & dosagem , Antagonistas GABAérgicos/administração & dosagem , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Muscimol/administração & dosagem , Pregnanolona/uso terapêutico , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacosRESUMO
We have recently shown that the neurosteroid allopregnanolone modulates anxiolytic effect of ethanol. In the present report, we attempted to examine whether neurosteroids progesterone and dehydroepiandrosterone sulphate (DHEAS), which modulate gamma-aminobutyric acid (GABA(A)) receptor function, affects development of tolerance to ethanol anxiolysis and withdrawal anxiety. Rats on ethanol (6% v/v in nutritionally balanced liquid diet) for prolong period (10 days) were injected twice daily either with vehicle, progesterone (a precursor of allopregnanolone, positive GABA(A) receptor modulator), finasteride (5alpha-reductase inhibitor) or DHEAS (negative GABA(A) receptor modulator). During this period, rats were acutely challenged periodically with ethanol (2 g/kg, i.p., 8% w/v) and subjected to the elevated plus maze test. For withdrawal studies, similar treatment protocols (except ethanol challenge) were employed and on day 11, rats were subjected to the elevated plus maze test at different time intervals post-ethanol withdrawal. While progesterone significantly advanced the development of tolerance to ethanol anxiolysis and enhanced withdrawal anxiety, DHEAS and finasteride prevented such behavioral alterations. These data highlight the important role played by GABAergic neurosteroids progesterone and DHEAS in the development of tolerance to ethanol anxiolysis and withdrawal anxiety in rats. Moreover, it points to the potential usefulness of specific neurosteroids as targets in the treatment of alcoholism.
Assuntos
Ansiedade/psicologia , Depressores do Sistema Nervoso Central/farmacologia , Sulfato de Desidroepiandrosterona/farmacologia , Etanol/farmacologia , Progesterona/farmacologia , Síndrome de Abstinência a Substâncias/psicologia , Animais , Tolerância a Medicamentos , Inibidores Enzimáticos/farmacologia , Finasterida/farmacologia , Pregnanolona/metabolismo , Pregnanolona/farmacologia , Progesterona/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/efeitos dos fármacosRESUMO
High concentrations of pituitary adenylate cyclase-activating polypeptide (PACAP) nerve fibers are present in the central nucleus of amygdala (CeA), a brain region implicated in the control of fear-related behavior. This study evaluated PACAPergic modulation of fear responses at the CeA in male Sprague-Dawley rats. PACAP (50-100 pmol) microinfusion via intra-CeA cannulae produced increases in immobility and time the rats spent withdrawn into a corner opposite to the electrified probe compared to controls in the shock-probe fear/defensive burying test. Shock-probe burying and exploration, numbers of shocks received, locomotion distance, and velocity were all reduced by intra-CeA PACAP injection. Further, intra-CeA PACAP effects were manifested only when the animals were challenged by shock, as intra-CeA PACAP injections did not cause significant changes in the behaviors of unshocked rats. Thus, intra-CeA administration of PACAP produces a distinct reorganization of stress-coping behaviors from active (burying) to passive modes, such as withdrawal and immobility. These findings are potentially significant toward enhancing our understanding of the involvement of PACAP and the CeA in the neural basis of fear and anxiety.
Assuntos
Adaptação Psicológica/efeitos dos fármacos , Tonsila do Cerebelo/efeitos dos fármacos , Medo/efeitos dos fármacos , Microinjeções , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/administração & dosagem , Adaptação Psicológica/fisiologia , Tonsila do Cerebelo/fisiologia , Animais , Eletrochoque/métodos , Medo/fisiologia , Masculino , Microinjeções/métodos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Ratos , Ratos Sprague-DawleyRESUMO
RATIONALE: Acute systemic ethanol administration is known to elevate plasma and cerebral levels of neuroactive steroid 3alpha-hydroxy-5alpha-pregnane-20-one (3alpha, 5alpha-THP; allopregnanolone) to a concentration sufficient to potentiate GABA(A) receptors. We have earlier demonstrated that 3alpha, 5alpha-THP mediates the antidepressant-like effect of ethanol in Porsolt forced swim test. OBJECTIVE: The aim of the present study is to explain the relationship between endogenous GABAergic neurosteroids and anxiolytic effect of ethanol in Sprague-Dawley rats. METHOD: The mediation of 3alpha, 5alpha-THP in the anti-anxiety effect of ethanol was assessed by pharmacological interactions of ethanol with various endogenous neurosteroidal modulators and using simulated physiological conditions of altered neurosteroid content in elevated plus maze (EPM) test. RESULTS: Pretreatment of 3alpha, 5alpha-THP (0.5-2.5 mug/rat, i.c.v.) or neurosteroidogenic agents such as 3alpha, 5alpha-THP precursor progesterone (5 or 10 mg/kg, i.p.), 11-beta hydroxylase inhibitor metyrapone (50 or 100 mg/kg, i.p.) or the GABA(A) receptor agonist muscimol (25 ng/rat, i.c.v.) significantly potentiated the anti-anxiety effect of ethanol (1 g/kg, i.p.). On the other hand, the GABAergic antagonistic neurosteroid dehydroepiandrosterone sulphate (DHEAS) (1 mg/kg, i.p.), the GABA(A) receptor blocker bicuculline (1 mg/kg, i.p.), the 5alpha-reductase inhibitor finasteride (50 x 2 mg/kg, s.c.) or the mitochondrial diazepam binding inhibitory receptor antagonist PK11195 (1 mg/kg, i.p.) reduced ethanol-induced preference of time spent and number of entries into open arms. Anti-anxiety effect of ethanol was abolished in adrenalectomized (ADX) rats as compared to sham-operated control. This ADX-induced blockade was restored by prior systemic injection of progesterone, signifying the contribution of peripheral steroidogenesis in ethanol anxiolysis. Socially isolated animals known to exhibit decreased brain 3alpha, 5alpha-THP and GABA(A) receptor functions displayed reduced sensitivity to the effects of ethanol and 3alpha, 5alpha-THP in EPM test. CONCLUSIONS: Our results demonstrated the contributory role of neuroactive steroid 3alpha, 5alpha-THP in the anti-anxiety effect of ethanol. It is speculated that ethanol-induced modulation of endogenous GABAergic neurosteroids, especially 3alpha, 5alpha-THP, might be crucial pertinent to the etiology of 'trait' anxiety (tension reduction) and ethanol abuse.
Assuntos
Ansiolíticos/farmacologia , Etanol/farmacologia , Pregnanolona/fisiologia , Adrenalectomia , Animais , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Progesterona/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/efeitos dos fármacos , Isolamento SocialRESUMO
Olanzapine increases brain allopregnanolone (ALLO) levels sufficiently to modulate neuronal activity by allosterically regulating GABAA receptors. Recently, we reported the antipsychotic-like profile of ALLO in rodents. The present study examined the hypothesis that olanzapine-induced elevation of endogenous neurosteroid ALLO is vital for its neuroleptic-like action. The conditioned avoidance response (CAR) and apomorphine-induced climbing behavioral paradigms were used in rodents. Administration of ALLO (1 microg, intracerebroventricular (i.c.v.)) or neurosteroidogenic agents such as the mitochondrial diazepam binding inhibitor receptor agonist, FGIN 1-27 (0.5 microg, i.c.v.) or the ALLO precursor, progesterone (10 mg/kg, i.p.) significantly potentiated olanzapine-induced blockade of CAR and apomorphine-induced climbing. In contrast, these agents failed to alter the antipsychotic-like effect of risperidone and haloperidol. On the other hand, inhibition of the endogenous biosynthesis of neurosteroids by the 3beta-hydroxysteroid dehydrogenase inhibitor, trilostane (30 mg/kg, i.p.), the 3alpha-hydroxysteroid oxidoreductase inhibitor, indomethacin (5 mg/kg, i.p.), or the GABAA receptor antagonist bicuculline (1 mg/kg, i.p.) and dehydroepiandrosterone sulfate (DHEAS) (1 mg/kg, i.p.) blocked the effect of olanzapine, but not of risperidone and haloperidol. Socially isolated animals, known to exhibit decreased brain ALLO and GABAA receptor functions, displayed a shortening in the muscimol-induced loss of righting reflex and an increased susceptibility to apomorphine-induced climbing. Administration of olanzapine, but not of haloperidol and risperidone, normalized the duration of muscimol-elicited loss of righting reflex. Although all three antipsychotics proved capable of antagonizing the apomorphine-induced climbing, a dose almost five times higher of olanzapine was required in socially isolated animals. The data obtained suggest that enhancement of the GABAergic tone plays a key role in the antipsychotic-like effect exerted by olanzapine in rodents, likely as a consequence of augmented levels of neuroactive steroids, in particular ALLO, in the brain. The present findings provide the first specific behavioral evidence in support of the hypothesis that neuroactive steroid ALLO- mediated GABAergic modulation is essential for the antipsychotic-like action of olanzapine.
Assuntos
Antipsicóticos/farmacologia , Benzodiazepinas/farmacologia , Pregnanolona/fisiologia , Animais , Apomorfina/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Antagonistas GABAérgicos/farmacologia , Antagonistas de Receptores de GABA-A , Haloperidol/farmacologia , Injeções Intraventriculares , Masculino , Atividade Motora/efeitos dos fármacos , Neurotransmissores/antagonistas & inibidores , Neurotransmissores/biossíntese , Olanzapina , Pregnanolona/metabolismo , Ratos , Ratos Sprague-Dawley , Risperidona/farmacologia , Isolamento Social , Ácido gama-Aminobutírico/fisiologiaRESUMO
Fluoxetine, a selective serotonin reuptake inhibitor, is known to increase the cortical content of allopregnanolone (ALLO) without altering the level of other neurosteroids. In contrast to the proconvulsant effect of many antidepressants, fluoxetine exhibits anticonvulsant effects. The present study was undertaken to examine the role of ALLO in the anticonvulsant action of fluoxetine against pentylenetetrazole (PTZ)-induced seizures in mice. Prior administration of GABA(A) receptor agonist muscimol or neurosteroid ALLO or progesterone, a precursor of ALLO or neurosteroidogenic drugs like FGIN 1-27, an agonist at the mitochondrial diazepam binding inhibitor receptor (MDR) or metyrapone, an 11beta-hydroxylase inhibitor, significantly potentiated the anticonvulsant effect of fluoxetine. In contrast, the effect of fluoxetine was counteracted by inhibition of the neurosteroid biosynthesis using drugs like 5alpha-reductase inhibitor, finasteride; 3beta-hydroxysteroid dehydrogenase inhibitor, trilostane; 3alpha-hydroxysteroid dehydrogenase inhibitor, indomethacin; MDR antagonist, PK 11195; or the GABA(A) receptor antagonist, bicuculline. Further, bilateral adrenalectomy had no significant effect on the anticonvulsant action of fluoxetine, suggesting negligible contribution from peripheral steroidogenesis. The anticonvulsant effect of fluoxetine was partially abolished in 5,7-DHT treated mice, indicating that the effect may also, in part, be dependent on serotonergic transmission. Thus, our data indicate that increased synthesis of ALLO in CNS is a major factor that ultimately leads to anticonvulsant effects of fluoxetine against PTZ-induced seizures.