Losing memory is definitely scary and as the world’s population ages, the burden of neurodegenerative disorders is becoming a critical global issue. Intense research is performed to deeply understand the molecular and cellular mechanisms underlying learning and memory functions. In fact, revealing novel molecular targets that might enable the fight against memory loss may pave the way to improve the quality of life of thousands and thousands of people suffering from neurodegenerative disorders such as Alzheimer’s disease and dementia.
In a recent PLOS ONE article, Lee and colleagues evaluated the anti-amnesic neuropharmacological properties of Gongjin-Dan (GJD), an asian remedy whose components were already described in the ancient korean book Dongui Bogam. Gongjin-Dan is composed of three medicinal herbs (Corni fructus, Korea angelica, and Ginseng radix) and two animal-derived materials (Muschus and Cornus cervi parvum). To test their hypothesis, Lee and colleagues used an animal model of hippocampal memory impairment which consists in injecting scopolamine, a potent antagonist of the cholinergic system. Under normal circumstances, the brain uses the neurotransmitter acetylcholine to facilitate learning and memory processes. As such, acetylcholine is essential to the process of memory formation. Scopolamine works antagonizing the neural functions of acetylcholine, thus blocking the first stages of memory formation, which usually take place in the hippocampus. The authors used two classical behavioral paradigms to assess memory function: the radial arm maze task and the passive avoidance test. In particular, the radial arm maze task reflects spatial learning and memory, whereas the passive avoidance test assesses fear-motivated memory retrieval in mice. Surprisingly, the Korean remedy GJD significantly reduced the scopolamine-induced amnesic behaviors observed in both behavioral tests.
Dissecting the molecular mechanisms of GJD
One question becomes of utmost importance: how does this ancient remedy work at the cellular and molecular levels? The authors had a first look at the cholinergic system, which is indeed the system that is profoundly altered by scopolamine. Interestingly, GJD treatment attenuated the enzymatic hyperactivation of AChE (Acetylcholinesterase) induced by scopolamine and it down-regulated the expression of the muscarinic acetylcholine receptor subtype 1 (mAChR1). Acetylcholine is capable of driving the activation of several intracellular signaling pathways responsible for a plethora of neuroadaptive cellular responses. Acetylcholine signaling eventually drives the phosphorylation of the cAMP response element binding protein (CREB), which then translocates into the nucleus to ultimately regulate the transcription of different genes. “In our results”, said the authors, “scopolamine significantly reduced the phosphorylation of CREB in the hippocampus, which was almost completely reversed by the GJD treatment”.
Lee and colleagues also evaluated whether other factors, such as the well-known neurotrophins BDNF and GNF, were involved with the beneficial effects of GJD. Neurotrophins have emerged as important regulators of synaptogenesis and synaptic plasticity mechanisms that underly learning and memory functions in the central nervous system. Interestingly, GJD treatment restored almost to completion the levels of BDNF and NGF, as well as of their receptors (TrkA and TrkB) in the hippocampus, which had been considerably decreased by scopolamine injection.
Effects of hippocampal neurogenesis
Another feature of memory decline is the alteration of neurogenesis, a critical process necessary for the generation of new cells in the brain. Adult hippocampal neurogenesis plays an important role in memory formation; therefore, impaired neurogenesis and neuronal integration are regarded as pathological features of neurodegenerative disorders. It is worth emphasizing that GJD was able to counteract the aberrations induced by the amnesic scopolamine, “as expected, the GJD treatment notably reversed the scopolamine-induced inhibition of neurogenesis in the subgranular zone of the hippocampal DG region and alterations in the hippocampal structure in CA1 and CA3” reported the authors.
Neurogenesis is strongly dependent on the activities of both neurotrophins and their receptors. Indeed, Dr. Chang-Gue Son, principal investigator at the Oriental Medical College of Daejeon University concluded that “the underlying mechanisms involve the regulation of the hippocampal cholinergic system and neurogenesis via activation of BDNF”
Traditional Asian medicine is built on a foundation of more than two millennia of medical and pharmacological practices that include various forms of herbal- and animal-derived remedies. However, many westerners scoff at the idea that an herbal remedy could have medicinal effects. Indeed, we crave more scientific validations for these ancient and respectable practices. For the moment let’s just say “why not?”. Science will produce its own answers…
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