Treatment with a GSK-3β/HDAC Dual Inhibitor Restores Neuronal Survival and Maturation in an In Vitro and In Vivo Model of CDKL5 Deficiency Disorder.
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SUBMITTER: Loi M
PROVIDER: S-EPMC8198396 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundCDKL5 deficiency disorder (CDD), a severe neurodevelopmental disorder characterized by early onset epilepsy, intellectual disability, and autistic features, is caused by mutations in the CDKL5 gene. Evidence in animal models of CDD showed that absence of CDKL5 negatively affects neuronal survival, as well as neuronal maturation and dendritic outgrowth; however, knowledge of the substrates underlying these alterations is still limited. Neuroinflammatory processes are known to contribute to neuronal dysfunction and death. Recent evidence shows a subclinical chronic inflammatory status in plasma from CDD patients. However, to date, it is unknown whether a similar inflammatory status is present in the brain of CDD patients and, if so, whether this plays a causative or exacerbating role in the pathophysiology of CDD.MethodsWe evaluated microglia activation using AIF-1 immunofluorescence, proinflammatory cytokine expression, and signaling in the brain of a mouse model of CDD, the Cdkl5 KO mouse, which is characterized by an impaired survival of hippocampal neurons that worsens with age. Hippocampal neuron survival was determined by DCX, NeuN, and cleaved caspase-3 immunostaining in Cdkl5 KO mice treated with luteolin (10 mg/kg), a natural anti-inflammatory flavonoid. Since hippocampal neurons of Cdkl5 KO mice exhibit increased susceptibility to excitotoxic stress, we evaluated neuronal survival in Cdkl5 KO mice injected with NMDA (60 mg/kg) after a 7-day treatment with luteolin.ResultsWe found increased microglial activation in the brain of the Cdkl5 KO mouse. We found alterations in microglial cell morphology and number, increased levels of AIF-1 and proinflammatory cytokines, and activation of STAT3 signaling. Remarkably, treatment with luteolin recovers microglia alterations as well as neuronal survival and maturation in Cdkl5 KO mice, and prevents the increase in NMDA-induced cell death in the hippocampus.ConclusionsOur results suggest that neuroinflammatory processes contribute to the pathogenesis of CDD and imply the potential usefulness of luteolin as a treatment option in CDD patients.
| S-EPMC8265075 | biostudies-literature
Project description:Several evidence pointed out the role of epigenetics in Alzheimer's disease (AD) revealing strictly relationships between epigenetic and "classical" AD targets. Based on the reported connection among histone deacetylases (HDACs) and glycogen synthase kinase 3β (GSK-3β), herein we present the discovery and the biochemical characterization of the first-in-class hit compound able to exert promising anti-AD effects by modulating the targeted proteins in the low micromolar range of concentration. Compound 11 induces an increase in histone acetylation and a reduction of tau phosphorylation. It is nontoxic and protective against H2O2 and 6-OHDA stimuli in SH-SY5Y and in CGN cell lines, respectively. Moreover, it promotes neurogenesis and displays immunomodulatory effects. Compound 11 shows no lethality in a wt-zebrafish model (<100 μM) and high water solubility.
| S-EPMC6466523 | biostudies-literature
Project description:BACKGROUND:Pathologic mutations in cyclin-dependent kinase-like 5 cause CDKL5 deficiency disorder, a genetic syndrome associated with severe epilepsy and cognitive, motor, visual, and autonomic disturbances. This disorder is a relatively common genetic cause of early-life epilepsy. A specific severity assessment is lacking, required to monitor the clinical course and needed to define the natural history and for clinical trial readiness. METHODS:A severity assessment was developed based on clinical and research experience from the International Foundation for CDKL5 Research Centers of Excellence consortium and the National Institutes of Health Rett and Rett-Related Disorders Natural History Study consortium. An initial draft severity assessment was presented and reviewed at the annual CDKL5 Forum meeting (Boston, 2017). Subsequently it was iterated through four cycles of a modified Delphi process by a group of clinicians, researchers, industry, patient advisory groups, and parents familiar with this disorder until consensus was achieved. The revised version of the severity assessment was presented for review, comment, and piloting to families at the International Foundation for CDKL5 Research-sponsored family meeting (Colorado, 2018). Final revisions were based on this additional input. RESULTS:The final severity assessment comprised 51 items that comprehensively describe domains of epilepsy; motor; cognition, behavior, vision, and speech; and autonomic functions. Parental ratings of therapy effectiveness and child and family functioning are also included. CONCLUSIONS:A severity assessment was rapidly developed with input from multiple stakeholders. Refinement through ongoing validation is required for future clinical trials. The consensus methods employed for the development of severity assessment may be applicable to similar rare disorders.
| S-EPMC6659999 | biostudies-literature
Project description:CDKL5 is a kinase with relevant functions in correct neuronal development and in the shaping of synapses. A decrease in its expression or activity leads to a severe neurodevelopmental condition known as CDKL5 deficiency disorder (CDD). CDD arises from CDKL5 mutations that lie in the coding region of the gene. However, the identification of a SNP in the CDKL5 5'UTR in a patient with symptoms consistent with CDD, together with the complexity of the CDKL5 transcript leader, points toward a relevant translational regulation of CDKL5 expression with important consequences in physiological processes as well as in the pathogenesis of CDD. We performed a bioinformatics and molecular analysis of the 5'UTR of CDKL5 to identify translational regulatory features. We propose an important role for structural cis-acting elements, with the involvement of the eukaryotic translational initiation factor eIF4B. By evaluating both cap-dependent and cap-independent translation initiation, we suggest the presence of an IRES supporting the translation of CDKL5 mRNA and propose a pathogenic effect of the C>T -189 SNP in decreasing the translation of the downstream protein.
| S-EPMC10642286 | biostudies-literature
Project description:CDKL5 deficiency disorder (CDD) was first identified as a cause of human disease in 2004. Although initially considered a variant of Rett syndrome, CDD is now recognised as an independent disorder and classified as a developmental epileptic encephalopathy. It is characterised by early-onset (generally within the first 2 months of life) seizures that are usually refractory to polypharmacy. Development is severely impaired in patients with CDD, with only a quarter of girls and a smaller proportion of boys achieving independent walking; however, there is clinical variability, which is probably genetically determined. Gastrointestinal, sleep, and musculoskeletal problems are common in CDD, as in other developmental epileptic encephalopathies, but the prevalence of cerebral visual impairment appears higher in CDD. Clinicians diagnosing infants with CDD need to be familiar with the complexities of this disorder to provide appropriate counselling to the patients' families. Despite some benefit from ketogenic diets and vagal nerve stimulation, there has been little evidence that conventional antiseizure medications or their combinations are helpful in CDD, but further treatment trials are finally underway.
| S-EPMC9788833 | biostudies-literature
Project description: Not available
| S-EPMC9661611 | biostudies-literature
Project description:CDKL5 deficiency disorder (CDD) is a developmental encephalopathy caused by pathogenic variants in the X-linked cyclin-dependent kinase 5 (CDKL5) gene. This rare disorder occurs more frequently in females than in males. The incidence is estimated to be approximately 1: 40,000-60,000 live births. So far, 50 cases have been described in boys. The clinical course in males tends to be more severe and is often associated with death in the first or second decade of life. The authors present an unreported 2.5-year-old male patient with drug-resistant epilepsy who was diagnosed with a de novo mutation in the CDKL5 gene. First seizures developed in the fifth week of life and have progressed steadily since then. The child's psychomotor development was strongly delayed, and generalized hypotonia was noticed since birth. Brain MRI showed areas of incomplete myelination, posterior narrowing of the corpus callosum, a pineal cyst of up to 3 mm, and open islet lids. Intensive antiseizure medications (ASMs), a ketogenic diet, and steroid therapy were not successful. Short-term improvement was achieved with the implantation of a vagal nerve stimulator (VNS). Due to the progressive course of the disease, the boy requires frequent modification of ASMs.
| S-EPMC9776588 | biostudies-literature
Project description:CDKL5 deficiency disorder (CDD) is a neurodevelopmental condition characterized by global developmental delay, early-onset seizures, intellectual disability, visual and motor impairments. Unlike Rett Syndrome (RTT), CDD lacks a clear regression period. Patients with CDD frequently encounter gastrointestinal (GI) disturbances and exhibit signs of subclinical immune dysregulation. However, the underlying causes of these conditions remain elusive. Emerging studies indicate a potential connection between neurological disorders and gut microbiota, an area completely unexplored in CDD. We conducted a pioneering study, analyzing fecal microbiota composition in individuals with CDD (n = 17) and their healthy relatives (n = 17). Notably, differences in intestinal bacterial diversity and composition were identified in CDD patients. In particular, at genus level, CDD microbial communities were characterized by an increase in the relative abundance of Clostridium_AQ, Eggerthella, Streptococcus, and Erysipelatoclostridium, and by a decrease in Eubacterium, Dorea, Odoribacter, Intestinomonas, and Gemmiger, pointing toward a dysbiotic profile. We further investigated microbiota changes based on the severity of GI issues, seizure frequency, sleep disorders, food intake type, impairment in neuro-behavioral features and ambulation capacity. Enrichment in Lachnoclostridium and Enterobacteriaceae was observed in the microbiota of patients with more severe GI symptoms, while Clostridiaceae, Peptostreptococcaceae, Coriobacteriaceae, Erysipelotrichaceae, Christensenellaceae, and Ruminococcaceae were enriched in patients experiencing daily epileptic seizures. Our findings suggest a potential connection between CDD, microbiota and symptom severity. This study marks the first exploration of the gut-microbiota-brain axis in subjects with CDD. It adds to the growing body of research emphasizing the role of the gut microbiota in neurodevelopmental disorders and opens doors to potential interventions that target intestinal microbes with the aim of improving the lives of patients with CDD.
| S-EPMC10978852 | biostudies-literature
Project description:BackgroundAcupuncture or electroacupuncture (EA) appears to be a potential treatment in acute clinical traumatic brain injury (TBI); however, it remains uncertain whether acupuncture affects post-TBI histone deacetylase (HDAC) expression or impacts other biochemical/neurobiological events.Materials and methodsWe used behavioral testing, Western blot, and immunohistochemistry analysis to evaluate the cellular and molecular effects of EA at LI4 and LI11 in both weight drop-impact acceleration (WD)- and controlled cortical impact (CCI)-induced TBI models.ResultsBoth WD- and CCI-induced TBI caused behavioral dysfunction, increased cortical levels of HDAC1 and HDAC3 isoforms, activated microglia and astrocytes, and decreased cortical levels of BDNF as well as its downstream mediators phosphorylated-Akt and phosphorylated-GSK-3β. Application of EA reversed motor, sensorimotor, and learning/memory deficits. EA also restored overexpression of HDAC1 and HDAC3, and recovered downregulation of BDNF-associated signaling in the cortex of TBI mice.ConclusionThe results strongly suggest that acupuncture has multiple benefits against TBI-associated adverse behavioral and biochemical effects and that the underlying mechanisms are likely mediated by targeting HDAC overexpression and aberrant BDNF-associated Akt/GSK-3 signaling.
| S-EPMC9396337 | biostudies-literature
Project description:CDKL5 deficiency disorder is a debilitating developmental and epileptic encephalopathy for which no targeted treatment exists. A number of promising therapeutics are under development for CDKL5 deficiency disorder but a lack of validated biomarkers of brain function and clinical severity may limit the ability to objectively assess the efficacy of new treatments as they become available. To address this need, the current study quantified electrophysiological measures in individuals with CDKL5 deficiency disorder and the association between these parameters and clinical severity. Visual and auditory evoked potentials, as well as resting EEG, were acquired across 5 clinical sites from 26 individuals with CDKL5 deficiency disorder. Evoked potential and quantitative EEG features were calculated and compared with typically developing individuals in an age- and sex-matched cohort. Baseline and Year 1 data, when available, were analysed and the repeatability of the results was tested. Two clinician-completed severity scales were used for evaluating the clinical relevance of the electrophysiological parameters. Group-level comparisons revealed reduced visual evoked potential amplitude in CDKL5 deficiency disorder individuals versus typically developing individuals. There were no group differences in the latency of the visual evoked potentials or in the latency or amplitude of the auditory evoked potentials. Within the CDKL5 deficiency disorder group, auditory evoked potential amplitude correlated with disease severity at baseline as well as Year 1. Multiple quantitative EEG features differed between CDKL5 deficiency disorder and typically developing participants, including amplitude standard deviation, 1/f slope and global delta, theta, alpha and beta power. Several quantitative EEG features correlated with clinical severity, including amplitude skewness, theta/delta ratio and alpha/delta ratio. The theta/delta ratio was the overall strongest predictor of severity and also among the most repeatable qEEG measures from baseline to Year 1. Together, the present findings point to the utility of evoked potentials and quantitative EEG parameters as objective measures of brain function and disease severity in future clinical trials for CDKL5 deficiency disorder. The results also underscore the utility of the current methods, which could be similarly applied to the identification and validation of electrophysiological biomarkers of brain function for other developmental encephalopathies.
| S-EPMC9374482 | biostudies-literature