Liposomal resveratrol protects dopaminergic neurons and may …
Boost Motor Function
Parkinson’s principal neuroanatomical characteristic is the
destruction of brain cells that produce the neurotransmitter dopamine
By Will Block
Our nature consists in motion; complete rest is death.
— Blaise Pascal
arkinson’s disease (PD) is the second most common neuerodegenerative disease after Alzheimer’s disease. PD’s principal neuroanatomical characteristic is the destruction of brain cells that produce the neurotransmitter dopamine in a small region of the midbrain called the substantia nigra. Dopamine is a powerhouse of functionality, governing a variety of crucial roles including reward (motivation), pleasure (euphoria), and motor mechanisms (movement). As age-related damage to the substantia nigra continues, the earliest symptoms of PD are movement related: tremors, shaking, muscular rigidity, slowness of movement, difficulty with walking, shuffling gait, and postural instability.
Motion is at the Root of Our Nature
A crucial difference between plants and animals is that animals have locomotion, the ability to move from one place to another. In the pool of mechanisms supported by dopamine, it is not by chance that motion is interlocked with gratification. Pleasure is a commanding motivator. As the French mathematician Pascal had conveyed: motion is at the root of our nature. Consequently, an understanding of how dopamine-producing cells are destroyed is crucial if we are to prevent the loss of our essentiality, by slowing down deterioration, improving repair, and perhaps even reversing destruction. Failing to do this means submitting to the juggernaut of aging and abandoning a central feature of our health. To be healthy is to be mobile.
When Dark Becomes Light
The appearance of the substantia nigra (Latin for “black substance”) is far darker than neighboring areas of brains tissue. This is due to high levels of melanin in dopaminergic neurons. Melanin is a pigment that is ubiquitous in nature. Curiously, the substantia nigra is not pigmented at birth, but develops its color with maturation. However, with the progression of PD, pigmented dopamine-producing cells are lost and thus the substantia nigra becomes lighter. How metaphorically ironic it is that our mobility lights go out as the darkness of the black substance fades.
Resveratrol Slows the Loss of Dopamine
New research has shown that resveratrol and liposomal resveratrol, can slow the loss of dopamine-producing cells in the substantia nigra. According to a very recent paper originating from Huazhong University of Science and Technology in Wuhan, China, treatment with resveratrol or resveratrol liposome for 14 days was found to produce significant improvement in the substantia nigra regions of PD model rats.
Using oral doses of 20 mg/kg per day (the equivalent of 243 mg/day for a 165 lb person), the loss and apoptosis (cell death) of nigral cells, and the levels of total reactive oxygen species (ROS) were markedly decreased. At the same time, the total antioxidant capability of nigral tissues significantly improved. Of significance, resveratrol liposome showed better effects than free resveratrol.
In the brain, oxidative stress may
denigrate the midbrain nigra
leading in due course to the death of
dopaminergic neurons, and thus
prove to be an underlying
causal factor of PD.
Pathologically, the selective, progressive loss of dopaminergic-producing neurons is also accompanied by the local formation of Lewy bodies, abnormal protein aggregates that form within nerve cells. The production of these bodies may in and of itself constitute a different neurodegenerative disease, Lewy Body Dementia. Nevertheless, when dopamine is reduced in the nigrostriatal pathways due to loss of dopaminergic neurons—beyond a certain point (by more than 70%)—those so beleaguered will manifest a series of clinical symptoms such as rigidity, tremor, bradykinesia (slowness in the execution of movement), and unstable gait.
Dopamine: Motion, Motivation, and Reward
Neurotransmitters are neural biochemicals, produced within the brain, which convey signals from one neuron to an intended cell. They cross what is known as a synapse, a junction between neurons and neurons or other types of cells. Viewed another way, neurotransmitters are message molecules that operate in the brain and throughout the central nervous system to pass on important information in parcel form. Packaged into vesicles that cluster beneath the presynaptic membrane of a synapse, neurotransmitters are released into the cleft that constitutes the synaptic divide. Once they cross the cleft, they bind to receptors in the postsynaptic membrane. When this occurs, the result is an action potential at the synapse, among other effects.
The precursors to neurotransmitters are typically amino acids, which are found in the diet—albeit sometimes in inadequate amounts for optimal effects—and require only a few steps for biosynthesis. Neurotransmitters may be classified several ways but dividing them into amino acids, peptides, and monoamines is convenient for some classification purposes. Among the major neurotransmitter amino acids are: glutamate, aspartate, D-serine, γ-aminobutyric acid (GABA), glycine. Among the monoamines and other biogenic amines: dopamine, norepinephrine (aka noradrenaline), epinephrine (aka adrenaline), histamine, serotonin. Others include acetylcholine, adenosine, nitric oxide, etc.
Structure of a typical chemical synapse
The list does not stop. Over 50 neuroactive peptides have been found to date, and new ones are often discovered. While many of these are “co-released” alongside a small-molecule transmitter, in some cases a peptide is the primary transmitter at a synapse. One well known example of a peptide neurotransmitter is β-endorphin. This molecule engages in highly specific interactions with opioid receptors in the central nervous system.
Some gaseous molecules such as nitric oxide (NO) and carbon monoxide (CO) are considered neurotransmitters, but these do not adhere to the strictest definition of classical neurotransmitters. This is because, although they have all been shown experimentally to be released by presynaptic terminals in an activity-dependent way, they are not packaged into vesicles.
By far the most prevalent transmitter is glutamate (which may be supplied as monosodium glutamate), which is excitatory at well over 90% of the synapses in the human brain. The next most prevalent is GABA, which is inhibitory at more than 90% of the synapses that do not use glutamate.
An important point: even though other transmitters are used in far fewer synapses, they may be very important functionally. Indeed the vast majority of psychoactive drugs produce their effects by altering the actions of some neurotransmitter systems, which do not involve glutamate or GABA.
The addictive drugs cocaine and amphetamine work primarily
on the dopamine system. Also, the addictive opiate drugs produce their effects primarily
as functional analogs
of opioid peptides, which, in turn, regulate dopamine levels.
The functions of dopamine in the brain are numerous, including important roles in behavior and cognition, motivation, punishment and reward, sleep, mood, attention, working memory, and learning.
Dopamine also inhibits prolactin production (involved in lactation and sexual gratification). Dopaminergic neurons (neurons whose primary neurotransmitter is dopamine) exist principally in the ventral tegmental area of the midbrain, the substantia nigra pars compacta, and the arcuate nucleus of the hypothalamus.
Oddly, it has been conjectured that dopamine transmits reward prediction error, whereby the phasic responses of dopamine neurons are observed when an unexpected reward is presented. These responses are thought to trigger a conditioned stimulus after repeated pairings with the reward.
Moreover, dopamine neurons become “depressed” when the expected reward is skipped. Do dopamine neurons encode the prediction error of rewarding outcomes? Science is still not sure, but we learn to repeat behaviors that lead to maximizing rewards. Consequently, dopamine is thought to provide a teaching signal enabling the brain responsible for acquiring new behavior to function. A teachable moment?
How PD Occurs
Recent research into the causality of the pathogenic process that results in PD has suggested a number of contributing factors that culminate in the selective loss of nigral dopaminergic neurons: oxidative stress, apoptosis, mitochondrial dysfunction, toxic exposure, environmental factors, excitatory neurotoxicity, and aging of the nervous system, along with immune abnormalities and inheritable factors.
Oxidative stress is indigenous to various diseases. Indeed, in the brain it is found to denigrate the midbrain nigra. This may in due course lead to the death of dopaminergic neurons, and thus prove to be an underlying causal factor of PD.
The dopamine molecule contains
unstable components that can be
readily oxidized to form ROS and
other compounds, which can further
oxidize dopamine to form the
neuronal toxin neuromelanin.
Furthermore, the selective destruction of dopamine-producing nigral brain cells is associated with the oxidative environment that takes place within the cells. The dopamine molecule contains unstable components that can be readily oxidized to form ROS and other compounds, which can further oxidize dopamine to form the neuronal toxin neuromelanin (remember that melanin gives the substantia nigra its dark color). Curiously, neuromelanin is predominantly cytoprotective within dopaminergic neurons, but when it is released from damaged neurons it activates microglia, which induces a vicious cycle of chronic neuroinflammation and additional neuronal loss. Altogether, ROS and other oxidants collude to induce oxidative stress, along with damage to components within the cell, including proteins, lipids, and DNA. Finally, these oxidants affect mechanisms by which mitochondrial housekeeping takes place, resulting in additional oxidative stress deterioration.
The many facets of resveratrol …
Resveratrol Fights Brain Inflammation
Growing evidence indicates that inhibition of microglia-mediated neuroinflammation may become a reliable protective strategy for Parkinson’s disease (PD). Resveratrol, a polyphenol naturally found in red wine and grapes, has been known to possess antioxidant, anticancer, and anti-inflammatory properties. While recent studies show that resveratrol provides neuroprotective effects against seizure, ischemia, and neurodegenerative disorders, the means by which it fights dopaminergic neurodegeneration are poorly understood.
In a new study, rat midbrain cultures were used to clarify the mechanisms underlying the neuroprotective properties of resveratrol. What the researchers found demonstrates that resveratrol protects dopamine neurons against neurotoxicity by inhibiting microglial activation, which in turn reduces proinflammatory factor release.
Mechanistically, resveratrol neuroprotection was thought to be caused by the inhibition of NADPH oxidase, a membrane-bound enzyme complex that catalyzes the univalent reduction of oxygen, using NADPH as an electron donor. Though their observations, the researchers noted that resveratrol reduced NADPH oxidase-mediated generation of reactive oxygen species. They also noted that resveratrol failed to exhibit neuroprotection in cultures from NADPH oxidase-deficient mice.
These findings suggest that resveratrol exerts neuroprotection against induced dopaminergic neurodegeneration, and that NADPH oxidase may be a major player in resveratrol-mediated neuroprotection.
- Zhang F, Shi JS, Zhou H, Wilson B, Hong JS, Gao HM. Resveratrol protects dopamine neurons against lipopolysaccharide-induced neurotoxicity through its anti-inflammatory actions. Mol Pharmacol 2010 Sep 1;78(3):466-77. Erratum in: Mol Pharmacol 2010 Nov;78(5):981.
Resveratrol Battles Free Radicals
Another recent study set out to investigate the neuroprotective effects of resveratrol on neurotoxin-induced Parkinson’s disease (PD) in rats. PD is an age-related neurodegenerative disorder in which the role of reactive oxygen species (ROS) is strongly implicated. Resveratrol has been shown to have antioxidant and anti-inflammatory actions and thus was tested for its beneficial effects.
Using a PD rat model, the experimental animals were pretreated with resveratrol (20mg/kg body weight injected into the body cavity) once daily for 15 days and then subjected to an injection of the neurotoxin 6-OHDA. Three weeks after that, the rats were tested for neurobehavioral activity and four weeks later they were sacrificed, whereupon several measurements were taken: lipid peroxidation, glutathione content, and the activity of antioxidant enzymes glutathione peroxidase, glutathione reductase, catalase, and superoxide dismutase.
Resveratrol was found to upregulate the antioxidant status while reducing the dopamine loss and this was supported by the analysis of the substantia nigra (the dopamine-producing area of the midbrain), where resveratrol protected its neurons from the deleterious effects of the neurotoxin.
Consequently, resveratrol may reduce the deterioration caused by free radicals, and thus help prevent subsequent behavioral, biochemical, and microscopic anatomical changes that transpire during PD.
- Khan MM, Ahmad A, Ishrat T, Khan MB, Hoda MN, Khuwaja G, Raza SS, Khan A, Javed H, Vaibhav K, Islam F. Resveratrol attenuates 6-hydroxydopamine-induced oxidative damage and dopamine depletion in rat model of Parkinson’s disease. Brain Res 2010 Apr 30;1328:139-51.
Resveratrol Saves Dopamine
When rat striatal slices were incubated in an oxygen-free (anoxic) medium, significant alterations in dopamine and a primary metabolite occurred: dopamine release increased several times, and its metabolite declined 50%. Also, tissue ATP (the “molecular unit of currency” of intracellular energy transfer) level was decreased 40% by anoxia.
However, when resveratrol was added to the medium, anoxia-induced dopamine release was decreased in a concentration-dependent manner. In contrary to dopamine output, anoxia-induced decline in tissue ATP level was not ameliorated by resveratrol. These and other discussed results indicate that some phenolic compounds, particularly resveratrol, decrease anoxia-induced dopamine output and hold promise as agents that can improve the alterations occurred under anoxic-ischemic conditions.
- Gürsoy M, Büyükuysal RL. Resveratrol protects rat striatal slices against anoxia-induced dopaminerelease. Neurochem Res 2008 Sep;33(9):1838-44.
Resveratrol Protects Against Neurodegeneration
A razor may have two sides. So may a molecule. For example, dopamine may operate as a neurotransmitter or as an oxidant that may contribute to the degeneration of dopaminergic neurons.
In a recent study, scientists have demonstrated that dopamine-induced cytotoxicity in human-derived neurotypic cells is prevented by resveratrol, one of the major antioxidative constituents found in the skin of grapes. When the human cells, a neuroblastoma cell line, were treated with dopamine for 24 hours, they underwent apoptosis (cell death) as determined by characteristic morphological features, including nuclear condensation, and loss of mitochondrial membrane potential (MMP). Analysis showed that dopamine can induce significant and severe apoptosis.
Conversely, exposure to resveratrol (5 microM) for 1 hour prior to the dopamine treatment reduced cytotoxicity, and rescued the loss of MMP. These results and others suggest that dopamine may be a potential oxidant of neuronal cells at biologically relevant concentrations.
But resveratrol may protect human-derived neurotypic cells against cytotoxicity, reducing intracellular oxidative stress through apoptosis, and may help prevent dopaminergic neurodegenerative disorder such as Parkinson disease.
- Lee MK, Kang SJ, Poncz M, Song KJ, Park KS. Resveratrol protects SH-SY5Y neuroblastoma cells from apoptosis induced by dopamine. Exp Mol Med 2007 Jun 30;39(3):376-84.
Resveratrol: A Plant Free Radical Scavenger
To go on, other factors such as environmental toxins and gene mutations can also result in selective damage to nigral dopaminergic neurons, and the resulting oxidative stress ultimately induces PD. Indeed, oxidative stress is so important in the pathogenesis of PD that research has been underway to find additional ways to slow and arrest it in order to treat PD. Resveratrol is one of the more interesting findings. It is a type of phytoalexin, a defensive phytochemical present in various plants that is characterized by its ability to scavenge free radicals and antioxidant activity. For this reason, resveratrol has wide natural pharmacological effects.
Numerous studies confirm that the
antioxidative activity of resveratrol
can help control of neuronal
Numerous studies confirm that the antioxidative activity of resveratrol can help control of neuronal degenerative diseases. In the Huazhong University study, the results showed that PD rats displayed some characteristics similar to those of human PD including reduced numbers of total nigral cells, reduced total nigral neurons and dopaminergic neurons in the nigral area, and significantly increased apoptosis of nigral cells. These resulted in abnormal behavior.
Also, the total ROS level was significantly increased, suggesting that an active oxidative status was present in the nigral area of PD rats. Nonetheless, after treatment with resveratrol, the behaviors of PD rats were significantly improved, while the numbers of total nigral cells, total nigral neurons and dopaminergic neurons in the nigral area were increased, and the apoptotic nigral cells were reduced.
Altogether, these results suggest that resveratrol can reduce the death of nigral dopaminergic neurons in PD rats, increase the count of viable neurons, and consequently improve abnormal behaviors. At the same time, resveratrol treatment reduced the total ROS level in the nigral area of PD rats and significantly improved the oxidative stress in the nigral area of PD rats.
Liposomal resveratrol can improve
the absorption rate, delay its release,
and enhance stability; all these add
up to improved bioavailability.
Liposomal Resveratrol Profoundly Better than Free Resveratrol
To drive the point home, resveratrol plays a protective role in the nigral dopaminergic neurons of PD rats, probably owing to the antioxidative effects of resveratrol. The Chinese study also indicated that resveratrol liposome had greater protective effects than free resveratrol on all the parameters except for behaviors. Liposomal resveratrol is a superfine microspherical preparation encapsulating resveratrol with a lipid bilayer, and has similar properties to resveratrol. However, resveratrol monomers are not water soluble, difficult to absorb after oral administration, and have low bioavailability, thus limiting their clinical application. Liposomal resveratrol can improve the absorption rate, delay its release, and enhance stability; all these add up to improved bioavailability. Meaning that liposomal resveratrol has more potent therapeutic effects, as the Chinese study’s results demonstrate. In summation, liposomal resveratrol may serve as a promising clinical agent for the oral treatment of PD, as compared to free resveratrol.
- Wang Y, Xu H, Fu Q, Ma R, Xiang J. Protective effect of resveratrol derived from Polygonum cuspidatum and its liposomal form on nigral cells in Parkinsonian rats. J Neurol Sci 2011 Mar 2. [Epub ahead of print]
- Pirkevi C, Lesage S, Brice A, Basak AN. From genes to proteins in Mendelian Parkinson’s disease: an overview. Anat Rec (Hoboken) 2009;292:1893–901.
Will Block is the publisher and editorial director of Life Enhancement magazine.