Type 1 diabetes: immune pathology and novel therapeutic approaches.

Type 1 diabetes (T1D) is characterized by the progressive destruction of insulin-producing beta cells in the pancreas. Despite improvements in insulin monitoring techniques, there remains no cure for T1D. Individuals with T1D require lifelong insulin therapy and some develop life-threatening complications. T1D is a complex, multifactorial, autoimmune condition. Understanding why people get T1D and how it progresses has advanced our knowledge of the disease and led to the discovery of specific targets that can be therapeutically manipulated to halt or reverse the course of T1D. Scientists investigating the potential of immunotherapy treatment for the treatment have recently had some encouraging results. Teplizumab, an anti-CD3 monoclonal antibody that has been approved by the FDA, delays the onset of clinical T1D in patients ≥ 8 years of age with preclinical T1D and improves beta cell function. Therapies targeting beta cell health, vitality, and function are now thought to be an essential component of successful combination therapy for T1D. The idea that the beta cells themselves may influence their own destruction during the development of T1D is a notion that has recently been gaining acceptance in the field. Researchers have recently made remarkable strides in beta cell replacement therapy and beta cell regeneration techniques. This review offers a detailed exploration of the pathophysiological mechanisms of T1D. It discusses the intricate interplay of factors leading to T1D development and the innovative approaches being explored to discover new treatments and a cure for the millions of people living with T1D worldwide.

Gene-environment interaction in the pathophysiology of type 1 diabetes.

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.

Blood glucose monitoring devices for type 1 diabetes: a journey from the food and drug administration approval to market availability.

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.

Diabetes mellitus, hearing loss, and therapeutic interventions: A systematic review of insights from preclinical animal models.

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.

A systematic review of the association of Type I diabetes with sensorineural hearing loss.

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).

Combined Levothyroxine and Propylthiouracil Treatment in Children with Monocarboxylate Transporter 8 Deficiency: A Multicenter Case Series of 12 Patients.

Objective: To evaluate the combined administration of propylthiouracil (PTU) and levothyroxine (LT4) in managing monocarboxylate transporter 8 (MCT8) deficiency and identify optimal therapeutic dosages. Methods: This multicenter case series involved 12 male patients with MCT8 deficiency whose parents/guardians consented to PTU and LT4 treatment. Data were collected from January 2008 to June 24, 2024. The study focused on treatment safety and outcomes, analyzing baseline and last encounter biochemical, metabolic, and anthropometric parameters. Statistical analyses included Wilcoxon signed ranks tests and generalized estimated equations to assess effects on thyroid and metabolic markers, and receiver operating characteristics curves to predict optimal dose. Results: Patients showed a significant reduction in serum total triiodothyronine (TT3) concentration and TT3/TT4 ratio, with increased serum TT4 and free T4 (fT4) concentrations. The use of PTU effectively reduced TT3 concentration by 25% at an average dose of 6.8 mg/kg/day, while LT4 increased fT4 concentration by 40% from baseline at an average dose of 4.3 µg/kg/day. Thyrotropin concentration was undetectable on treatment. No statistical differences were observed in metabolic and physical parameters between baseline and last encounter overall for the group, but six of eight patients for whom these data were available had an increase in weight (z-score). There were no adverse effects on liver function or granulocyte numbers noted throughout the period of observation. Conclusion: Combined treatment with PTU and LT4 normalized serum T3, fT4, and TT4 in patients with MCT8 deficiency. Individualized dose adjustments were crucial for achieving therapeutic goals, indicating the need for personalized treatment plans.

Systematic review of translational insights: Neuromodulation in animal models for Diabetic Peripheral Neuropathy.

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.

Immunological and virological triggers of type 1 diabetes: insights and implications.

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.

Eyes on the Prize: Decoding the Ophthalmic Product Regulations and Intricacies of the U.S. Food and Drug Administration Approval.

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.

Measurement of Reverse Triiodothyronine Level and the Triiodothyronine to Reverse Triiodothyronine Ratio in Dried Blood Spot Samples at Birth May Facilitate Early Detection of Monocarboxylate Transporter 8 Deficiency.

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.

Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: A double-blind, phase 1/2a, randomized controlled trial.

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.

Neurosteroid allopregnanolone mediates anxiolytic effect of etifoxine in rats.

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.

Chronic progesterone treatment augments while dehydroepiandrosterone sulphate prevents tolerance to ethanol anxiolysis and withdrawal anxiety in rats.

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.

Microinfusion of pituitary adenylate cyclase-activating polypeptide into the central nucleus of amygdala of the rat produces a shift from an active to passive mode of coping in the shock-probe fear/defensive burying test.

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.

Evaluation of GABAergic neuroactive steroid 3alpha-hydroxy-5alpha-pregnane-20-one as a neurobiological substrate for the anti-anxiety effect of ethanol in rats.

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.

Role of neuroactive steroid allopregnanolone in antipsychotic-like action of olanzapine in rodents.

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.

Essentiality of central GABAergic neuroactive steroid allopregnanolone for anticonvulsant action of fluoxetine against pentylenetetrazole-induced seizures in mice.

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.

Diabetic peripheral neuropathy and neuromodulation techniques: a systematic review of progress and prospects.

Neuromodulation for diabetic peripheral neuropathy represents a significant area of interest in the management of chronic pain associated with this condition. Diabetic peripheral neuropathy, a common complication of diabetes, is characterized by nerve damage due to high blood sugar levels that lead to symptoms, such as pain, tingling, and numbness, primarily in the hands and feet. The aim of this systematic review was to evaluate the efficacy of neuromodulatory techniques as potential therapeutic interventions for patients with diabetic peripheral neuropathy, while also examining recent developments in this domain. The investigation encompassed an array of neuromodulation methods, including frequency rhythmic electrical modulated systems, dorsal root ganglion stimulation, and spinal cord stimulation. This systematic review suggests that neuromodulatory techniques may be useful in the treatment of diabetic peripheral neuropathy. Understanding the advantages of these treatments will enable physicians and other healthcare providers to offer additional options for patients with symptoms refractory to standard pharmacologic treatments. Through these efforts, we may improve quality of life and increase functional capacity in patients suffering from complications related to diabetic neuropathy.