Long-term exposure to environmental pollutants is worldwide acknowledged as a major risk factor for health diseases. Indeed, pollution has become a plague. Many clinical studies have focused on the impact of pollution on vital organs such as the lungs and heart. Strong positive correlations between pollutants and cancer (just to make an unfortunate example) are not mysteries anymore. However, new results provide strong evidence that nanoparticles, which can easily find their way into the central nervous system, may lead to severe brain problems. In fact, chronic exposure to harmful metal nanoparticles such as lead, cadmium or iron may impact the normal functioning of our nervous system, eventually leading to cognitive decline as well as to neurodevelopmental dysfunctions.
Lead (Pb) is a well-established environmental pollutant and, because of its high affinity to the N-methyl-D-aspartate (NMDA) receptor, Pb can modify basic cellular properties such as cell communication, neuronal transmission and synaptic plasticity. Importantly, alteration of synaptic plasticity has been shown to be detrimental for learning and memory processes.
In a recent article published in PLOS ONE, Yang and colleagues report that beta-asarone, a natural compound found in Chinese herbal formulas, such as Kai-Xin-San and Chong-Myung-Tang, was able to ameliorate behavioral and cellular alterations observed in Pb-induced cognitive dysfunctions.
beta-asarone reverses Pb-induced structural and behavioral alterations.
Using the Golgi-Cox staining technique, the authors report that Pb exposure significantly decreased spine density in the hippocampus, a brain region highly involved in learning and memory functions. Surprisingly, this detrimental effect induced by lead was significantly reduced when rats were treated with beta-asarone. “This result indicated that beta-asarone treatments repaired Pb-induced impairments in spine formation in developmental hippocampus”, says Qian-Qian Yang, the leading author of the study. Dendritic spines arise as small protrusions from the dendritic shaft of various types of neurons and receive inputs from excitatory axons. They contain neurotransmitter receptors, organelles, and signaling systems essential for synaptic function and plasticity.
In order to correlate the results obtained on dendritic synaptogenesis with a possible behavioral phenotype, the Morris Water-Maze test was employed to evaluate spatial learning and memory in rats. Interestingly, Pb-exposed rats showed a dramatic reduction of spatial memory functions, while beta-asarone treatment was able to retrieve the Pb-induced spatial memory deficits in a dose-dependent manner. Altogether these data suggest that beta-asarone may act as a neuroprotective agent. How that might happen?
beta-asarone reverses Pb-induced molecular modifications.
Several proteins are involved in the regulation of dendritic spines structure and formation, such as Arc/Arg3.1 and Wnt7a. In addition, such factors are closely related to the activation of the glutamate receptors NMDA-R and AMPA-R. The authors observed that NR2B (a specific subunit of the NMDA receptor) was reduced after Pb exposure in the rat hippocampus, while beta-asarone supplement restored the reduction in a dose-dependent manner. Parallel to that, also the levels of the immediate-early gene Arc/Arg3.1 were found to be restored following beta-asarone treatment. It must be noted that Arc/Arg3.1 is a key molecule to maintain efficient and intact synaptic plasticity, a form of cellular learning.
Another signaling pathway involved in synaptogenesis is the Wnt signaling cascade. This pathway is one of the central morphogenic signaling pathways regulating early neuronal development and Wnt7a preferentially stimulates excitatory dendritic spine formation. “In the present study”, says Dr. Chen, the senior author of the study, “the relative expression of Wnt7a in hippocampal CA1 area of Pb-exposed rats significantly decreased by 43.2%, which is consistent with our previous results, while beta-asarone treatment dose-dependently recovered the decreasing”.
At the cellular level, beta-asarone has been also reported to reverse decreased BDNF and promote hippocampal neurogenesis in chronic unpredictable mild stress exposed rats (Dong H et al., 2014) and to activate the extracellular signal-regulated kinase (ERK), a critical kinase involved in neurogenesis (Mao J et al., 2015). “These reports together with our results suggest BDNF/Wnt signaling pathway might represent a key target for various neurogenesis agents, including beta-asarone”, concludes Qian-Qian Yang.
Although the study tries to dig into the intimate cellular mechanisms responsible for the neuroprotective action of beta-asarone, the authors were not able to point to a direct mechanism by which this natural compound may be the key actor for the structural and behavioral effects observed. In agreement with this last point, the authors state that “Although the exact molecular targets of beta-asarone in promoting neurogenesis are still unclear, our study provided preliminary hints for their underlying mechanisms”.
In a world where environmental pollution has become a serious and dramatic health problem, investing in basic research may lead to the discovery of natural agents able to reduce pollutants’ side effects. Obviously, such pharmacological strategies will be completely useless and unfortunate if not paralleled by drastic changes in environmental regulation and policy.
Let’s for once conceive of a greener world.
- Mao J, Huang S, Liu S, Feng XL, Yu M, Liu J, et al. A herbal medicine for Alzheimer’s disease and its active constituents promote neural progenitor proliferation. Aging Cell. 2015;14(5):784–96. doi: 10.1111/acel.12356. pmid:26010330
- Dong H, Gao Z, Rong H, Jin M, Zhang X. beta-asarone reverses chronic unpredictable mild stress-induced depression-like behavior and promotes hippocampal neurogenesis in rats. Molecules. 2014;19(5):5634–49. doi: 10.3390/molecules19055634. pmid:24786848
- Yang QQ, Xue WZ, Zou RX, Xu Y, Du Y, Wang S, Xu L, Chen YZ, Wang HL, Chen XT. β-Asarone Rescues Pb-Induced Impairments of Spatial Memory and Synaptogenesis in Rats. PLoS One. 2016 Dec 9;11(12):e0167401. doi: 10.1371/journal.pone.0167401. eCollection 2016.
Any views expressed are those of the author, and do not necessarily reflect those of PLOS.
Giuseppe Gangarossa received his PhD in Biomedical Sciences, specialty Neuroscience, from the University of Bologna. He has been a visiting fellow at the Karolinska Institutet (Sotckholm, Sweden), the French Inserm (Montpellier, France) and the Collège de France (Paris, France). Giuseppe is currently Assistant Professor of Physiology at the University Paris Diderot. His main research topic is dopamine-related brain disorders. You can follow him on twitter @PeppeGanga