Parkinson’s disease, formerly known as “shaking palsy”, was discovered by Dr. James Parkinson in 1817. It is the second most chronicprogressive neurodegenerative medical complication. No standard diagnostic criteria has been developed so far to define Parkinson’s in the clinical practice, and so the current diagnosis is based on the presence of cardinal manifestations, such as bradykinesia, rigidity, and tremor. To date, there is no potential cure for the disease, but several treatment approaches and therapies have been taken into consideration to provide relief from both motor and non-motor symptoms, but none could provide effective long term benefits. It has previously been proved through sundry cases that when different systems of medicines are combined, a patient’s health is drastically improved. As a novel approach to control the progression of the disease, the allopathic medications and surgeries can be combined with the traditional medicinal sciences like ayurvedic and homeopathic sciences. The article summarizes the potent neuroprotective effects of Nux vomica in the treatment of Parkinson’s disease.
Parkinson’s Disease (PD), formerly known as “paralysis agitans” or“shaking palsy” is a chronic progressive neurodegenerative disorder of the Central Nervous System (CNS) which is caused as a result of damage to the basal ganglia cells of the human brain. The disease is characterized by a combination of symptoms, which include bradykinesia being the hallmark symptom of PD; cogwheel rigidity; resting tremor, and postural instability that can occur due to idiopathic reasons . Other symptoms also include excessive drooling, shuffling gait, muscle weakness, impaired speech, sleep disturbances, constipation, and liver damage. Additionally, some psychological symptoms such as abrupt mood changes like depression, apathy, hallucinations, confusion, delusions, and anxiety can be noticed in some patients. Dementia, which is caused by a significant loss of brain function, also represents one of the prominent symptoms when a patient reaches advanced stages of PD.
PD affects the basal ganglia, and its neurochemical origin was discovered in 1960 by O. Hornykiewicz, who showed that the dopamine content of substantia nigra and corpus striatum in post mortem brains of PD patients was extremely low, and was associated with a loss of dopaminergic neurons . Later on, after elaborated studies, it was discovered that the neurons which extend from the substantia nigra to the putamen and caudate nucleus release the neurotransmitter dopamine (DA), which was degenerated in PD. The caudate nucleus of the basal ganglia contains neurons that liberate the neurotransmitter acetylcholine (Ach). Although the level of Ach does not change as the level of DA declines, the imbalance of neurotransmitter activity causes most of the PD symptoms . The current treatment of PD is directed towards increasing the level of DA and decreasing the level of Ach. Since people with PD do not manufacture enough DA, taking it orally is useless as it cannot pass through the blood-brain barrier . The article emphasizes the therapeutic significance of the strychnos nux vomica in the treatment of Parkinson’s disease.
Etiology of Parkinson’s Disease
To date, the cause of PD is unknown, but certain factors have been identified as the probable cause of this disease. These factors are categorized as genetic mutations, environmental factors, and pathogenic factors. It has been estimated that approximately 20% of PD cases are caused by genetic influences and mutations . These cases could be associated with single-gene mutations and complex gene interactions with certain risk factors such as multiple gene mutations, gene-gene interactions, gene-environment interactions, and gene-epigenetic interactions. The idiopathic PD and the genetic PD cannot generally be distinguished on clinical grounds, but the genetic PD human model can be used to study the idiopathic PD .
The pathogenic factors in PD include oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammation, protein aggregation, and apoptosis . There is evidence that, in the brain, each of the above-mentioned processes is taking place and is involved in pathogenesis, but there is no evidence regarding which one comes first and in which order these processes take place. Additionally, all the attempts that have been made to influence the course of the disease by blocking one of these strategies have failed so far. Each of these factors act together in a network, so interference with any one of them is not sufficient to be able to provide neuroprotection . This network of events leads to cell death and it is believed that the apoptotic cell signaling plays an important role in the death mechanism. This can also be a secondary phenomenon but the real mechanism of why cells die still remains unknown .
Some studies reveal that PD may also be induced by drugs like halogenated phenothiazines, chlorpromazine, promazine, mepazine, methoxypromazine, triflupromazine, pimozide, triperidol, haloperidol, reserpine, procaine, methyldopa, and tetrabenazine. Additionally, toxic environmental chemicals such as herbicides, pesticides- paraquat, rotenone, organochlorine pesticides, organophosphates, chlorinated solvents, cyanide, methanol, carbon monoxide, metals- manganese, lead, iron, polychlorinated biphenyls, air pollution and particulate matter, and previous mild to moderate head injuries can also lead to symptoms of PD . New light was thrown on the possible etiology of PD by a chance event. In 1982, a group of young drug addicts in California suddenly developed an exceptionally severe form of PD, and the cause was traced to the compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which was a contaminant in illegal preparation of a heroin substitute. MPTP causes irreversible destruction of nigrostriatal dopaminergic neurons in various species and produces a PD-like state in primates . These cases were then classified under the category of drug-induced Parkinson’s and are potentially reversible conditions when offering agents are removed. However, this may take a year or longer to resolve.
Current Treatment Approaches
The current pharmacological approach to treat PD is based on the concepts of symptomatic therapy (i.e. to control the symptoms of the disease.) Doctors usually recommend combinations of various supportive therapies like physiotherapy, occupational therapy, and speech-language therapies. They may also recommend lifestyle changes and may advise patients to go to speech-language pathologists to improve their speech difficulties .
One of the milestones of dopaminergic treatment was first achieved in 1961 when a human patient experienced levodopa infusion and oral levodopa replacement therapy. In 1968, levodopa was approved for PD patients as it could provide partial relief from the motor complications being a DA precursor, but it failed to slow down the progression of the disease. Later on, different potential drugs were discovered to slow down the progression of the disease similar to DA agonists (pramipexole, rotigotine), glutamate antagonists (amantadine), catechol-o-methyltransferase (COMT) inhibitors (entacapone or tolcapone). Monoamine oxidase B (MAO-B) inhibitor selegiline and rasagiline are also known to improve brain functions upon administration. Some studies revealed that when PD patients were administered selegiline in their early stages, they showed 35% better motor functioning .
Modern approaches include Deep Brain Stimulation (DBS), a prime non-destructive surgical treatment that involves implanting electrodes in specific brain areas. Other novel treatment approaches include cell replacement therapies using stem cell technology, gene introduction, gene replacements and substitutions to provide long term benefits to patients.
Potential Benefits of Strychnos Nux Vomica
Understanding the cause and mechanism of cell death e is one of the most important aspects of trying to develop a neuroprotective drug that could slow down, stop, or even cure PD. Recently herbs and ayurvedic drugs have gained a lot of attention and consideration as potent neuroprotective agents to treat complex neurodegenerative disorders like Parkinson’s and Alzheimer’s. Strychnos nux vomica, also known as nux vomica, poison nut, semen strychnos, and quaker buttons, is a deciduous plant native to the Malabar Coast in Southern India and other Southeastern Asian countries like Sri Lanka and Indonesia. It is a major source of highly poisonous, intensely bitter alkaloid strychnine, brucine, and loganin and is derived from the seeds inside the tree’s round, green to orange fruit. However the medicinal properties of nux vomica are substantially due to the abundance of alkaloids strychnine and brucine  . Strychnine is a highly toxic, colorless, bitter, crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents . When inhaled or ingested at a higher dose through the eyes or mouth, strychnine causes poisoning which results in muscular convulsions and eventually death through asphyxia. Strychnine binds to Aplysia californica, Ach binding protein, and is a homolog of nicotinic receptors with high affinity and low specificity and does so in multiple conformations .
Nux vomica is used in some traditional medicinal systems that prevailed in India and China. The drug was previously used for the treatment of health conditions like allergies, back pain, constipation, common cold, stress, hemorrhoids, menstrual pain, headaches, flu, and digestive troubles. The alkaloid in nux vomica, strychnine, is a nerve tonic and stimulant, capable enough to affect the functioning of both the developing and the mature nervous tissues. It acts as an antagonist of glycine and Ach receptors. Through various studies, it has been revealed that it primarily affects motor nerve fibers in the spinal cord that control the process of muscle contraction. In order to generate an impulse, excitatory neurotransmitters must bind to their respective receptor of the nerve cells. However, in the presence of inhibitory neurotransmitters, the process of generating the action potential becomes difficult. Therefore, a greater concentration of neurotransmitters is required to bind to the receptors in order to generate the needed potential. In PD, due to the loss of dopaminergic neurons, their level in comparison to Ach reduces and this causes Parkinsonism symptoms. Strychnine, upon administration, can antagonize Ach and glycine (inhibitory neurotransmitters) and bind non-covalently to their receptors to prevent the postsynaptic neuron from inhibitory effects of glycine. Therefore action potentials can be triggered with lower levels of excitatory neurotransmitters. The use of nux vomica can prove to be beneficial in the management of the response fluctuations of levodopa and DA agonist therapies. The response fluctuations like honeymoon, wearing OFF, ON-OFF fluctuations, delayed ON, NO-ON phenomenon (dose failure) are commonly seen in the advanced stage PD . At such stages, medication therapies fail to control the fluctuating motor symptoms and dyskinesia. Thus the patient becomes very vulnerable and they often die due to infections and other medical complications. The aim of therapies at this stage is optimal symptom control and they can be improved using herbal medications like nux vomica.
Pharmacokinetics of Nux Vomica
The administration of strychnine is carried out orally, by inhalation or systemic (via injection) routes. It is a potentially bitter substance and hence, on the administration to humans, it activates bitter taste receptors TAS2R10 and TAS2R46 . Strychnine is rapidly absorbed from the gastrointestinal tract . Due to the slight protein binding, it leaves the bloodstream quickly and distributes it in the tissues . It has been recorded that approximately 50% of the ingested strychnine dose can enter the tissues within 5 minutes . The drug is actively transported by plasma and erythrocytes. It is rapidly metabolized by the liver microsomal enzyme system requiring NADPH and oxygen . The biological half-life of strychnine is about 12 hours [14}. After a few minutes of ingestion, strychnine is excreted, unchanged in the urine, and accounts for about 5-15% of the sub-lethal dose given over 6 hours. Excretion or elimination follows first-order kinetics and is virtually completed in 48-72 hours  .
Nux vomica is a widely known herbal medicine used to treat a wide range of medical complications including cancer. The prime concern with the use of the drug is its toxicity. The toxicological studies of nux vomica have revealed that strychnine is highly toxic to humans and animals. Poisoning by inhalation, swallowing, or absorption through eyes and mouth can be fatal. The deaths of individuals after Strychnine nux vomica administration is primarily caused by respiratory arrest. The other possible causes of death include cardiac arrest, multiple organ failure, or brain damage. Despite being used to treat severe diseases and disorders, the toxicity of strychnine is not ethically studied by researchers worldwide, and thus the plant appears on the commission E-list of unapproved herbs because it has not proven to be safe or effective.
All its medical and toxicological effects have been well studied in the traditional Indian medical system, Ayurveda. The Ayurvedic science is based on the fundamental principle known as the “Panchamahabhuta Siddhant,” which states that all material forms, including the body, are composed of 5 subtle elements: Prithvi (Earth), Jala (Water), Vayu (Air), Agni (Fire), and Aakash (Space). The “Tridosha Theory” establishes a relationship between these five elements. “Dosha” is an ayurvedic term used to describe an individual’s inherited traits and tendencies. In simpler terms, dosha means impurity, and an imbalance in dosha can result in diseased states or conditions. The “Tridosha Theory” explains the relationship of these elements as 3 Dosa-
Vata - air and space: movement of air and the space within the body
Pitta - fire and moisture: transformation, moisture, and energy within the body
Kapha - earth and water: strength (immunity) within the body
In Ayurveda, a drug called hudar has been identified as a mixture containing Strychnos nux vomica. The seeds used in the treatment are first immersed in water for five days and then immersed in milk for the next two days, followed by boiling in milk . Through this approach, the toxic content can be lowered and then it can be considered safe and effective and is recommended for its use. The Ayurvedic studies of the drug reveal that it is a Vatashaamaka ( i.e. it alleviates the Vata-Tridosha concept of Ayurveda and reduces pain.) In addition, due to its sharp properties, hudar stimulates and strengthens the nerves and is useful in treating various disorders, including neuralgia, facial palsy, hemiplegia, paralysis, insomnia, epilepsy, diabetes, anemia, constipation, chlorosis, spermatorrhea, and other infections. The lethal dose of hudar in humans is about 30-120 mg, and an overdose can lead to intoxication and convulsions .
Parkinson’s disease is a chronic, progressive neurodegenerative disorder caused by the degeneration of the dopaminergic neurons in the substantia nigra pars compacta of the brain. Since the cause of the disease is unknown, the modern treatment approaches focus on symptomatic therapies. As a novel treatment approach, allopathic sciences can be combined with the ayurvedic and homeopathic sciences to develop potent neuroprotective agents. The ayurvedic studies suggest that there are several drugs that have an effect on nerve cells and which upon safe administration, can alter the progression of neurological disorders. Strychnos nux vomica is one such native herbal drug found in the tropical forest of the Malabar Coast in Southern India and Southeastern Asian countries. Recent studies reveal some neuropharmacological effects of the drug and have postulated it as a nerve tonic that might be useful in the development of neuroprotective drugs. Elaborated study on this herb, especially on the toxicological parameter, can give promising results with lesser side effects. This article summarizes the potential benefits of the herb and its use as a novel neuroprotective agent for the treatment of Parkinson’s disease combined with other systems of medicines.
Shambhavi Chaturvedi is a student pursuing bachelor's in Pharmacy from the Sanskar College of Pharmacy and Research, India. She is a member of International Parkinson's and Movement Disorder Society (MDS), American Academy of Neurology (AAN), European Academy of Neurology (EAN) and certain National Organizations. She is working to contribute to the field of science and aims to be a researcher in the near future. She has also attended various national conferences related to the field of medicine and health and has also presented posters. She has also participated and won various presentational certificates, particularly for oral presentations. Her current articles and posters aim to target audience on the effect of Parkinson's and Alzheimer's diseases in the society.