Protective role of madecassoside from Centella asiatica against protein L-isoaspartyl methyltransferase deficiency-induced neurodegeneration

Protein L-isoaspartyl methyltransferase (PIMT/PCMT1) could repair l-isoaspartate (L-isoAsp) residues formed by deamidation of asparaginyl (Asn) residues or isomerization of aspartyl (Asp) residues in peptides and proteins during aging. Aside from abnormal accumulation of L-isoAsp, PIMT knockout (KO) mice mirrors some neuropathological hallmarks such as anxiety-like behaviors, impaired spatial memory and aberrant synaptic plasticity in the hippocampus of neurodegenerative diseases (NDs), including Alzheimer's disease (AD) and related dementias, and Parkinson's disease (PD). While some reports indicate the neuroprotective effect of madecassoside (MA) as a triterpenoid saponin component of Centella asiatica, its role against NDs-related anxiety and cognitive impairment remains unclear. Therefore, we investigated the effect of MA against anxiety-related behaviors in PIMT deficiency-induced mouse model of NDs. Results obtained from the elevated plus maze (EPM) test revealed that MA treatment alleviated anxiety-like behaviors in PIMT knockout mice. Furthermore, Real-time PCR, electroencephalogram (EEG) recordings, transmission electron microscopy analysis and ELISA were carried out to evaluate the expression of clock genes, sleep and synaptic function, respectively. The PIMT knockout mice were characterized by abnormal clock patterns, sleep disturbance and synaptic dysfunction, which could be improved by MA administration. Collectively, these findings suggest that MA exhibits neuroprotective effects associated with improved circadian rhythms sleep-wake cycle and synaptic plasticity in PIMT deficient mice, which could be translated to ameliorate anxiety-related symptoms and cognitive impairments in NDs.