Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by Fragile X Messenger Ribonucleoprotein (FMRP) deficiency. Electroencephalogram (EEG) changes in FXS include alterations of oscillatory activity and responses to sensory stimuli, some of which have been back-translated into rodent models by knocking-out the Fragile X messenger ribonucleoprotein 1 gene (Fmr1-KO). However, the validity of these EEG phenotypes as objective biomarkers requires further investigation. Potential pharmacotherapies such as mGluR5 inhibitors (e.g. CTEP; 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazole-4-yl)ethynyl)pyridine), GABA_BR agonists (e.g. arbaclofen) and δ-containing GABA_AR agonists (e.g. gaboxadol) have not translated into clinical success despite rescuing many phenotypes in the Fmr1-KO model. Yet none of these treatments have been assessed on EEG phenotypes in the Fmr1-KO model. Therefore, we set out to discover new EEG phenotypes in Fmr1-KO mice, using "task-free" and auditory-evoked (AEPs) and visually-evoked potential (VEP) paradigms, and probe their modulation by CTEP, arbaclofen and gaboxadol, using within-subjects designs. First, we report Fmr1-KO-associated EEG abnormalities that closely resemble those observed in FXS, including elevated gamma-band power, reduced alpha/beta-band coherence, increased AEPs and delayed VEPs. Secondly, we found that pharmacological treatment, at best, only partially normalized EEG phenotypes. CTEP restored alpha/beta-band coherence and AEP amplitudes but failed to normalize gamma power and VEP latencies. Conversely, arbaclofen reduced gamma power but did not restore coherence or AEP amplitudes and further delayed VEPs. Gaboxadol did not normalize any EEG phenotypes. We conclude that these compounds have limited ability to normalize these EEG phenotypes.

2024-11-01·Journal of Biochemical and Molecular Toxicology

Multimodal action of phosphodiesterase 5 inhibitors against neurodegenerative disorders: An update review

Review

作者: Varshney, Prachi ; Bhushan, Bharat ; Singh, Pranjul ; Singh, Niraj Kumar ; Singh, Ashini

AbstractPhosphodiesterase type 5 (PDE5) is an enzyme primarily found in the smooth muscle of the corpus cavernosum and also highly expressed in the substantia nigra, cerebellum, caudate, hippocampal regions and cerebellar purkinje cells, responsible for selectively breaking down cyclic guanosine monophosphate (cGMP) into 5′‐GMP and regulate intracellular cGMP levels. As a second messenger, cyclic GMP enhances signals at postsynaptic receptors and triggers downstream effector molecules, leading to changes in gene expression and neuronal responses. Additionally, cGMP signaling transduction cascade, present in the brain, is also essential for learning and memory processes. Mechanistically, PDE5 inhibitors share structural similarities with cGMP, competitively binding to PDE5 and inhibiting cGMP hydrolysis. This action enhances the effects of nitric oxide, resulting in anti‐inflammatory and neuroprotective effects. Neurodegenerative disorders entail the progressive loss of neuron structure, culminating in neuronal cell death, with currently available drugs providing only limited symptomatic relief, rendering neurodegeneration considered incurable. PDE5 inhibitors have recently emerged as a potential therapeutic approach for neurodegeneration, neuroinflammation, and diseases involving cognitive impairment. This review elucidates the principal roles of 3′,5′‐cyclic adenosine monophosphate (cAMP) and cGMP signaling pathways in neuronal functions, believed to play pivotal roles in the pathogenesis of various neurodegenerative disorders. It provides an updated assessment of PDE5 inhibitors as disease‐modifying agents for conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral ischemia, Huntington's disease, and neuroinflammation. The paper aims to review the current understanding of PDE5 inhibitors, which concurrently regulate both cAMP and cGMP signaling pathways, positing that they may exert complementary and synergistic effects in modifying neurodegeneration, thus presenting a novel direction in therapeutic discovery. Moreover, the review provides critical about biological functions, therapeutic potentials, limitations, challenges, and emerging applications of selective PDE5 inhibitors. This comprehensive overview aims to guide future academic and industrial endeavors in this field.

2024-10-17·The journal of sexual medicine

Regenerative therapies for erectile dysfunction: a systematic review, Bayesian network meta-analysis, and meta-regression.

Article

作者: La, Troy ; Hinojosa-Gonzalez, David E ; Kronstedt, Shane ; Khera, Mohit ; Orozco Rendon, Daniela ; Saffati, Gal ; Muthigi, Akhil

BACKGROUNDCurrent guidelines advocate a shared decision-making process approach to erectile dysfunction management, and while there is growing interest in regenerative therapies such as stem cell therapy, platelet-rich plasma injections, and low-intensity shockwave therapy for erectile dysfunction, comparative data on the efficacy of these modalities are limited.AIMThis systematic review and network meta-analysis aims to compare stem cell therapy, platelet-rich plasma injections, and low-intensity shockwave therapy for managing erectile dysfunction and quantify their impact on the International Index of Erectile Function (IIEF).METHODSIn January 2024, a systematic search of online databases was performed to identify randomized clinical trials related to stem cell therapy, platelet-rich plasma injections, and low-intensity shockwave therapy in erectile dysfunction. Eligible articles reported outcomes using the IIEF score. Data were inputted into Review Manager 5.4 for pairwise meta-analysis. Data were then used to build a network in R Studio. These networks were used to model 200 000 Markov Chains via MonteCarlo sampling. The results are expressed as standardized mean difference (SMD) with 95% credible intervals (CrI). Meta-regression was used to adjust for PDE5is use.OUTCOMESImpact on the International Index of Erectile Function.RESULTSA total of 16 studies involving 907 patients were analyzed. The standardized mean difference (SMD) vs control for stem cell therapy was 0.92 [95% CrI -0.49, 2.3]. For platelet-rich plasma, the SMD vs control was 0.83 [95% CrI 0.15, 1.5], and for low-intensity shockwave therapy, the SMD vs control was 0.84 [95% CrI 0.49, 1.2]. When stratifying low-intensity shockwave therapy by dose, the SMD vs control at 0.15 mJ/mm2 was 1.1 [95% CrI 0.36, 1.9], while at 0.09 mJ/mm2, it was 0.75 [95% CrI 0.26, 1.2]. Meta-regression adjusting for the administration of PDE5 inhibitors yielded non-significant results.CLINICAL IMPLICATIONSThe findings suggest that stem cells, platelet-rich plasma, and low intensity shockwave therapy, particularly at 0.15 and 0.09 mJ/mm2, may offer improvements in erectile function.STRENGTHS AND LIMITATIONSThe strength is the robust statistical methods. Limitations are in heterogeneity in control groups and follow-up durations among included studies.CONCLUSIONShockwave therapy and platelet-rich plasma demonstrated statistically significant improvements, though the clinical relevance and extent of their impact remain questionable. Further research is necessary to determine the efficacy of stem cell therapies for erectile function.

100 项与 ERK5 inhibitors(Newcastle University) 相关的药物交易

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