Luteolin Treatment Ameliorates Brain Development and Behavioral Performance in a Mouse Model of CDKL5 Deficiency Disorder

Abstract

CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental disease caused by mutations in the X-linked CDKL5 gene, is characterized by early-onset epilepsy, intellectual disability, and autistic features. Although pharmacotherapy has shown promise in the CDD mouse model, safe and effective clinical treatments are still far off. Recently, we found increased microglial activation in the brain of a mouse model of CDD, the Cdkl5 KO mouse, suggesting that a neuroinflammatory state, known to be involved in brain maturation and neuronal dysfunctions, may contribute to the pathophysiology of CDD. The present study aims to evaluate the possible beneficial effect of treatment with luteolin, a natural flavonoid known to have anti-inflammatory and neuroprotective activities, on brain development and behavior in a heterozygous Cdkl5 (+/−) female mouse, the mouse model of CDD that best resembles the genetic clinical condition. We found that inhibition of neuroinflammation by chronic luteolin treatment ameliorates motor stereotypies, hyperactive profile and memory ability in Cdkl5 +/− mice. Luteolin treatment also increases hippocampal neurogenesis and improves dendritic spine maturation and dendritic arborization of hippocampal and cortical neurons. These findings show that microglia overactivation exerts a harmful action in the Cdkl5 +/− brain, suggesting that treatments aimed at counteracting the neuroinflammatory process should be considered as a promising adjuvant therapy for CDD.

Exploration of the Core Pathways and Potential Targets of Luteolin Treatment on Late-Onset Depression Based on Cerebrospinal Fluid Proteomics

“…For instance, liposomal preparations using olive pomace oil [ 26 ], dietary formulations with LUT [ 27 ], and ultra-micronized preparations [ 28 ] can all enhance the oral absorption and safety of LUT. Previous studies have shown that LUT possesses biological activities such as neuroprotection, anti-neuroinflammation, and the prevention of neuronal death [ 16 , 29 ]. LUT holds great promise for the treatment of brain-related disorders such as cerebral ischemia, Alzheimer’s disease, depression, and autism spectrum disorders [ 30 , 31 , 32 ].…”

“…Previous research has shown that LUT possesses a variety of pharmacological activities, such as anti-inflammation, anti-oxidation, anti-aging, neuroprotective, neurotrophic, and neurogenic actions [ 14 , 15 ]. LUT can enhance or even rehabilitate hippocampal neurogenesis, as well as promote dendritic spine maturation and reduce hippocampal neuronal death, thus providing neuroprotective effects against brain injury [ 16 ].…”

Rett and Rett-related disorders: Common mechanisms for shared symptoms?

“…Abnormal systemic inflammation and brain neuroinflammation have been described in Rett syndrome and CDD in all three disorders. [106][107][108][109][110][111][112][113] In fact, Rett syndrome has been suggested to be an autoimmune disease. 114 Reduced FOXG1 expression in experimental models increases sensitivity of neurons to inflammatory stimuli.…”

TRRAP-mediated acetylation on Sp1 regulates adult neurogenesis

“…The activation of quiescent aNSCs and the proper self-renewal and differentiation capacity of aNSCs are important for the functional adult brain [12] , [13] . Several diseases, such as Intellectual Disability (ID) and Autism Spectrum Disorders (ASD), show impaired adult hippocampal neurogenesis [14] , [15] , [16] . The cytoarchitecture of the septal and striatal SVZ, as a region of neonatal neurogenesis, is often altered in ASD patients [17] .…”