ArticleCNS neuroscience & therapeutics2022
Treatment with FRAX486 rescues neurobehavioral and metabolic alterations in a female mouse model of CDKL5 deficiency disorder.
Article in CNS neuroscience & therapeutics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 14 citations in OpenAlex.
- α‑Cyperone targets the PAK1‑JNK/NF‑κB axis to modulate dendritic cells maturation and Th2/Th9 differentiation in an asthma model.International journal of molecular medicine · 2026Article
- Acupuncture modulates actin homeostasis and promotes myelin sheath regeneration in rat models of intracerebral hemorrhage.Journal of molecular histology · 2026Article
- PAK1 inhibitor NVS-PAK1-1 preserves dendritic spines in amyloid/tau exposed neurons and 5xFAD mice.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Excitatory cortical neurons from CDKL5 deficiency disorder patient-derived organoids show early hyperexcitability not identified in neurogenin2 induced neurons.Neurobiology of disease · 2025Article
- Effects of a ciliary neurotrophic factor (CNTF) small-molecule peptide mimetic in an in vitro and in vivo model of CDKL5 deficiency disorder.Journal of neurodevelopmental disorders · 2024Article
- Voluntary Running Improves Behavioral and Structural Abnormalities in a Mouse Model of CDKL5 Deficiency Disorder.Biomolecules · 2023Article
- The molecular basis of p21-activated kinase-associated neurodevelopmental disorders: From genotype to phenotype.Frontiers in neuroscience · 2023Review
- Treatment with FRAX486 rescues neurobehavioral and metabolic alterations in a female mouse model of CDKL5 deficiency disorder.CNS neuroscience & therapeutics · 2022Article
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
introductionCDKL5 deficiency disorder (CDD) is a rare neurodevelopmental condition, primarily affecting girls for which no cure currently exists. Neuronal morphogenesis and plasticity impairments as well as metabolic dysfunctions occur in CDD patients. The present study explored the potential therapeutic value for CDD of FRAX486, a brain-penetrant molecule that was reported to selectively inhibit group I p21-activated kinases (PAKs), serine/threonine kinases critically involved in the regulation of neuronal morphology and glucose homeostasis.
methodsThe effects of treatment with FRAX486 on CDD-related alterations were assessed in vitro (100 nM for 48 h) on primary hippocampal cultures from Cdkl5-knockout male mice (Cdkl5-KO) and in vivo (20 mg/Kg, s.c. for 5 days) on Cdkl5-KO heterozygous females (Cdkl5-Het).
resultsThe in vitro treatment with FRAX486 completely rescued the abnormal neuronal maturation and the number of PSD95-positive puncta in Cdkl5-KO mouse neurons. In vivo, FRAX486 normalized the general health status, the hyperactive profile and the fear learning defects of fully symptomatic Cdkl5-Het mice. Systemically, FRAX486 treatment normalized the levels of reactive oxidizing species in the whole blood and the fasting-induced hypoglycemia displayed by Cdkl5-Het mice. In the hippocampus of Cdkl5-Het mice, treatment with FRAX486 rescued spine maturation and PSD95 expression and restored the abnormal PAKs phosphorylation at sites which are critical for their activation (P-PAK-Ser144/141/139) or for the control cytoskeleton remodeling (P-PAK1-Thr212).
conclusionsPresent results provide evidence that PAKs may represent innovative therapeutic targets for CDD.
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