By definition, a nootropic is a compound that increases mental function. They are most often used to boost memory, motivation, concentration and attention. There are two different types: synthetic nootropics (such as Piracetam, a labcreated compound) and natural and herbal nootropics, like Ginkgo biloba and American ginseng. Natural nootropics are capable of improving cognitive function while making the brain healthier.
Nootropics act as a vasodilator against the small arteries and veins in the brain. The introduction of natural nootropics into the system increases blood circulation, provides important nutrients and increases energy and oxygen flow to the brain. Despite only accounting for 3% of total body weight, the brain receives around 15% of the body’s supply of oxygen and blood. In fact, the brain can only generate energy from burning glucose, proving that neurons depend on the continuous supply of oxygen and nutrients. In contrast to most of other cells in the body, neurons cannot be reproduced and are irreplaceable.
Neuron cells constantly use converted energy to repair cell compartments. The energy generated from glucose is crucial for maintenance, and electrical and neurotransmitter activity. Natural nootropics have been shown to reduce the occurrence of inflammation in the brain. The use of nootropics also helps to protect the brain from toxins, minimises the effects of brain ageing and improves brain function by stimulating new neuron cells. As brain activity increases, so does cognitive and memory ability, thus strengthening neuroplasticity.
Commercialised natural nootropics currently on the market react to different mechanisms and, therefore, affect different parameters. Natural nootropics alter the concentration of existing neurotransmitters, stimulating the release of dopamine, the uptake of choline, cholinergic transmission, phosphatase A2 activity, phosphatidylinositol turnover and the function of AMPA receptors. Some natural nootropics also act as a positive allosteric modulator for acetylcholine or glutamate receptors. The release of neurotransmitters and the increased activity induced by natural nootropics facilitates the long-term potentiation (LTP) and improves synaptic transmission.
The establishment of a new natural nootropic must take into account the cellular and molecular mechanism of cognitive processes. This article suggests several mechanisms to mediate the effects of nootropics in cognitive performance.
Receptor of new ideas
Glutamatergic transmission is an example of synaptic plasticity associated with LTP. Glutamate is an essential neurotransmitter involved in cognitive processes. There are two different types of glutamate receptors, ionotropic and metabotropic, distributed on the pre and post-synaptic sites of the neuron.
These receptors are responsible for the neuronal network that facilitates cognitive performance. The release of glutamate will activate the NMDA and AMPA receptors – AMPA receptors are responsible for synaptic transmission, while NMDA receptors are responsible for classic learning and memory. The brain responds by opening the Na+/K+ ion channel and depolarising the cell membrane. However, hyperactive glutamate receptors can cause oxidative stress to occur in response to cognitive dysfunction. The NMDA receptor is an ionotropic channel and distributes abundantly in the hippocampus, cortex and thalamus to assist the movement of Ca+2, Na+, and K+ ions.
Activation of the NMDA receptor is reported to initiate LTP in the hippocampus. LTP is part of the synaptic plasticity responsible for physiological changes in cognitive function associated with learning and memory. The increased Ca+2 permeability and the blockage of voltage-dependent Mg+2 contribute to the synaptic plasticity and formation of memories. Higher levels of Ca+2 affect the gene and protein expression for LTP and, subsequently, may lead to neurotoxicity due to overexcitation of glutamate – as observed in Alzheimer’s disease. The blockage of NMDA receptors has also been shown to result in cognitive impairment in animal models, and is associated with dementia and schizophrenia. Downregulated glutamate has been observed in Alzheimer’s patients, accompanied by the reduction of NMDA receptors in the hippocampus. AMPA receptors, another type of ionotropic channel, are known to mediate the fast and immediate postsynaptic response to glutamate release, and thus, may contribute to synaptic plasticity. The receptor can be found throughout the brain, especially in the thalamus, hypothalamus, cerebral cortex, hippocampus, basal ganglia and cerebellum, also permeable for Na+ and K+. The increased density of AMPA receptors in the hippocampus has been shown to enhance the consolidation of memories. The use of AMPA modulators causes the deactivation and desensitisation of the receptor in the hippocampus, which facilitates cognitive performance, including short-term memory.
Examples of nootropics
■ Pyrrolidinone derivatives: a class of fivemembered lactams with a four-carbon heterocyclic ring structure found in many pharmaceuticals and natural products. The synthesis of nootropics from pyrrolidinone derivatives has some common features, including enhancing the learning process, diminishing impaired cognition and protecting against brain damage. A number of pyrrolidine derivatives are commercially available, including piracetam, oxiracetam, aniracetam and promiracetam. Administering aniracetam or piracetam affects the muscarinic receptor binding in the different brain regions.
■ Bacopa monnieri: is derived from the family of Scrophulariaceae, found throughout the Indian subcontinent in wet, damp and marshy areas. The plant is used for a number of nervous system disorders, including insomnia, anxiety and epilepsy. According to Ayurvedic medical practitioners, Bacopa monnieri stimulates and enhances the memory and intellect. These properties have been studied both preclinically and clinically. The plant contains bacoside A and bacoside B, compounds that have neuroprotective as well as antiinflammatory actions. In addition to enhancing cognition and memory functions, Bacopa monnieri is known for its anxiolytic effects and use in managing convulsive sickness. The nootropic effect of the plant is mediated by the enhancement of protein kinase activity and the production of protein in the hippocampus.
■ Ginkgo biloba: described as a ‘living fossil’ as its morphology and features have remained unchanged for over 100 million years. The plant is well known for its medical use, as well as being a source of food. Despite a lack of research studying its effects, Ginkgo biloba is claimed to have neuroprotective effects in both human and animal models, and has been listed under a group of anti-dementia drugs. It acts as an antioxidant, has antiapoptotic properties, and induces inhibition effects against caspase-3 activation and amyloid-beta-aggregation in cases of Alzheimer’s disease. Ginkgo biloba is also proposed to have an antiamyloidogenic property, whereby the plant extract prevents production of amyloid fibrils.
■ Panax ginseng: has an important position in traditional Chinese medicine, and more recent reports have suggested that it may be effective in improving the cognitive function of Alzheimer’s disease patients. Its antioxidant property is claimed to suppress Alzheimer’s-like pathology, while the intake of the plant in healthy individuals may increase memory capacity. The active constituents of the plant are ginsenoside saponins, which are divided into panaxadiol, panaxatriol and oleanolic acid groups. It has been suggested that a high ratio of panaxatriol to panaxadiol is responsible for the enhancement of memory and cognitive abilities.
■ Rhodiola rosea: reported to improve cognitive function, enhance memory and learning, and protect the brain against future damage. The plant has been shown to increase the level of 5-hydroxytryptamine and norepinephrine in the cerebral, prefrontal and frontal cortex. At the same time, the intake of Rhodiola rosea causes the upregulation of dopamine and acetylcholine in the limbic system pathways, which are responsible for emotional calming. A study showed that the introduction of the plant may protect the nervous system against oxidative damage, thus lowering the risk of Alzheimer’s. The plant also and reduces memory impairment and encourages learning in Alzheimer’s patients. Like Bacopa monnieri and Panax ginseng, Rhodiola rosea is considered to be an ‘adaptogen’ that enhances endurance and resistance against stressful situations.
Our understanding of the mechanisms influenced by the use of natural nootropics has expanded tremendously in the past decade. Nootropics can help a number of systems in the body, including blood circulation, and have been shown to boost energy levels. There are also a number of mechanisms influenced by nootropics, such as glutaminergic signalling and amyloid precursor protein – vital for patients of neuro-related diseases such as dementia and Alzheimer’s.
The original paper, ‘Establishing natural nootropics: recent molecular enhancement influenced by natural nootropic’ in Evidence-Based Complementary and Alternative Medicine, can be found online.
