Molecular Mechanisms of Neuroprotection and Cognitive Enhancement by an Alternative drug Centella asiatica

Abstract

Complementary and Alternative medicine (CAM) is increasingly gaining enormous importance as a part of current day therapeutic regimen for various incurable, chronic neurological disorders, majorly because of the palliative treatment offered by them. Centella asiatica, is one of the herbal plants reported in Ayurveda as “Medhya Rasayana” attributing to its CNS related beneficial effects especially on intellect, learning and memory. Previous reports have found the whole plant extract of Centella asiatica (CA) to beneficially modulate the cognition and enhance the quality of life in healthy elderly volunteer. Recent reports on pharmacological investigation of Centella asiatica extract (CaE) in animal studies have established the cognitive enhancing effects of CaE in battery of behavioral tests. However, there is limited information regarding the molecular mechanism of action of Centella asiatica. In the current study, we studied the neuroprotective and mnemonic mechanisms of CaE in both in vitro and in vivo experimental settings. CaE was commercially obtained and tested for its bioactive chemical constituents through various biochemical tests. CaE was found to be an effective inhibitor of 15-LOX and Caspase-3 activity, thus exhibiting potent anti-inflammatory and anti-apoptotic capability. CaE, in immortalized hippocampal cell (H19-7 cell) line, induced activation of CAMKII/CREB/BDNF pathway subsequently resulting in modulation of NMDA receptors subunits expression. Against hydrogen peroxide (H2O2), a potent inducer of oxidative stress, CaE demonstrated neuroprotective effects and effectively neutralized the ROS generation. In addition, CaE in 5 and 10 µg/ml concentrations efficaciously attenuated the H2O2 induced increase in caspase-3 levels. Taken together, our study for the first time demonstrated CaE to possess multi-target approach entailing to its anti-oxidative, anti-inflammatory and anti-apoptotic effects. Also, CaE induces the CREB activity through PKA/CAMKII pathway which possibly via modulating the excitatory transmission enhances the synaptic plasticity in the CNS. Our previous report has established the CaE effect in lowering of amyloid load in double transgenic mouse model of Alzheimer’s disease (AD). However, the mechanism of lowering β-amyloid load by CaE in the transgenic mice remains unexplored. Therefore, in the present study we studied the effect of CaE on two major pathophysiological pathways underlying the progression of cognitive deficits in the double transgenic APPswe+PS1dE9 model. Firstly, the effect of CaE on the synaptic plasticity in hippocampus was assessed. We found a significant increase in the CREB phosphorylation accompanied with the changes in NMDA receptors subunits in the CaE treated transgenic mice. Also, we found the enhancement in long term potentiation (LTP) process in the hippocampus of the CaE treated transgenic mice along with the better performance in battery of behavioral tests analyzing learning and memory. Secondly, we studied the effect of CaE on the T-cell induced inflammation in the APPswe+PS1dE9 mouse model. Moreover, CaE attenuated the activation of T-cell helper cells and increased the activity of T-regulatory cells to combat the β-amyloid induced neuro-inflammation. Thus, the current study established the protective role of CaE against β-amyloid induced neurotoxicity and shows that this alternative herbal drug has significant unexploited therapeutic potential in cognitive neurological disorders.