Motor Neurone Disease: Treatment by Modern and Conventional Medicines

 

Alimuddin Saifi

NKBR College of Pharmacy and Research Centre, Meerut

*Corresponding Author E-mail: asaifi2005@gmail.com

 

ABSTRACT:

Motor neuron disease (MND) is a neurodegenerative disease. It is a fatal and progressive disease that attacks specific nerve cells (motor neurons) in the spinal cord and the brain. Motor neurons control the voluntary movement of muscles. MND is also known as Lou Gehrig´s disease, maladie de Charcot and amyotrophic lateral sclerosis (ALS).‘Amyotrophic’ refers to the loss of muscle mass; ‘lateral’ refers to the nerve tracks that run down both sides of the spinal cord, where many of the neurons affected by MND are found; ‘sclerosis’ refers to the scar tissue that remains after the nerves damage. Motor neurons reach to the spinal cord from brain and to the muscles throughout the body from spinal cord. When motor neurons are not working, the capacity of the brain to initiate and control muscle movement is lost. Patients are often initially prompt­ed to seek medical advice because of a persistent muscle twitch, muscle fatigue, or even muscle wasting. This generally initiates in the hands or lower legs, frequently accompanied by cramps. As MND progresses, patients lose the ability to dress and feed themselves, sit up, walk, or even speak. The bodily functions that remain intact until or near death are the control of urination and bowel movements, sexual function, eye movement, and intellect. Gen­erally, patients survive three to five years after diagnosis. Death generally occurs due to respiratory failure. MND is most common in the age range of 40 to 70 years and about 20 per cent more common in men than in women. The cause of the disease is still unclear. Present treatment of MND is aimed at symptomatic relief, prevention of complica­tions and maintenance of optimal function and optimal quality of life. Researchers have shown that the antibiotic stops “cell suicide” (neuronal apoptosis). Apoptosis includes the activa­tion of nitric oxide and caspase enzyme. The present paper includes the information about the possible treatment of MND by herbal medicines.

 

KEYWORDS: MND, Amyotrophic lateral sclerosis, Motor neurons, Herbal drug.

 

 


 

 

 

 

 

 

 

 

INTRODUCTION:

Motor Neuron Disease (MND) is an adult onset neurodegenerative disorder which leads inevitably passing through weakness of limbs, bulbar and respiratory muscle to death from respiratory failure after three to five years. About 10% cases of MND are hereditary. Management of MND focuses on symptomatic relief and quality of life.[1]  It is a chronic neurodegenerative disorder of the motor system in adults, characterized by the loss of motor neurons in the cortex, brain stem, and spinal cord.[2] It was first explained by Charcot in the nineteenth century and is also known by the eponym “Lou Gehrig’s Disease” after the famous baseball player who was affected with the disease. Death usually results from respiratory failure and follows on average two to four years after onset, but some may survive for a decade or more.[3] MND is a comparatively uncommon disease with a reported population incidence of between 1.5 and 2.5 per 100,000 per year[4] and a prevalence of 2.7-7.4 per 100,000 population.[5] Age is the most significant risk factor and the disease occurs throughout adult life, with the peak incidence between 50 to 75 years of age.[6] MND occurs more commonly in men than in women in a ratio of 3:2.[7] About 10 per cent of MND cases are inherited. Of those, 20 per cent are caused by mutations in a gene on chromosome 21 named SOD1 (super oxide dismutase 1). Over 60 mutations or structural defects of the SOD enzyme have been found which alter the enzyme’s ability to protect against damage to motor neurons. [8] Two types of motor nerve cells are involved in ALS (Figure 1). The upper motor neuron is located in the brain and sends nerve fibers descending the spinal cord. The lower motor neuron, located in the brain stem and spinal cord, sends nerve fibers out to muscles. Upper motor neurons converse to lower motor neurons, and lower motor neurons converse to muscles. Loss of either type of nerve cells results in weakness, and weakness is the major symptom of ALS. MND is also known as amyotrophic lateral sclerosis (ALS). The word ‘amyotrophic’ refers to muscle shrinkage when lower motor neurons die. The word ‘lateral’ refers to the lateral part of the spinal cord where upper motor neuron fibers pass through the spinal cord. When upper motor neurons die, scar tissue fills in where the nerve fibers used to be in the spinal cord. The scar tissue is firm to the touch, and the term ‘sclerosis’ means hardening (as in hardening of the arteries in atherosclerosis). [9]

 

 

Figure 1: Upper left is an outline of the brain and the spinal cord.

 

The site of the upper motor neurons is given away. In the center is an outline of a slice through the spinal cord. The site of the lateral corticospinal tracts is exposed. They have descending fibers from the upper motor neurons. The site of the lower motor neurons is shown as diamonds. In the right half of the spinal cord, dotted lines indicate death and collapse of upper and lower motor neurons, which leads to shrinkage of muscle.[9]

Clinical characteristics:

MND results degeneration of upper motor neurones in the motor cortex and lower motor neurones of the brainstem and spinal cord, or both. In a study, 94% of patients had the ALS variant of MND. Two other variants of MND are primary lateral sclerosis (PLS) and progressive muscular atrophy (PMA). One study demonstrated that PLS accounts for about 2% of MND cases and PMA for 4% of cases.[10] PLS is a wholesome upper motor neurone disorder and shows progressive upper motor neurone degeneration with limb and bulbar dysfunction, with no effect on lower motor neurones. Compared to patients with an ALS variant, PLS patients tend to present five to ten years earlier and survive six to seven years longer. PLS patients have less limb wasting and bulbar symptoms during the course of the disease. [11] PMA is related with a degeneration of the lower motor neurones of the spinal cord. It has no effect on upper motor neurone and bulbar region. It is slowly progressive and can be as long as 20 to 30 years, but this is not always the case.[12]

 

The conventional thought that MND only affects the motor system is obsolete. MND is now believed to be a multisystem neurodegenerative disease. There is rising clinical evidence for autonomic dysfunction.[13]

 

Diagnosis and symptoms:

Motor neurone disease is mostly an infrequent disease of middle and old age, though it may be present in younger patients. Motor neurone disease may be identified by understanding of clinical symptoms, signs and use of examinations to eliminate other causes. When patients are seen very early after onset of symptoms with limited signs, a definitive test should be carried out. Waiting and observation of the condition over weeks and months are needed in these cases.[14]

 

 

Figure 2: Lower motor neurone loss leads to muscle wasting, particularly of first dorsal interossei (top), tibialis anterior (middle), and tongue (bottom)

 

Respiratory Symptoms:

During the course of ALS, respiratory muscle weakness develops which causes dyspnoea, orthopnoea. Symptoms of carbon dioxide retention include daytime somnolence, morning headaches and lack of restorative sleep with frequent waking. The management of respiratory complications includes early recognition and treatment of aspiration pneumonia with antibiotics, chest physiotherapy and postural drainage to clear secretions, sleeping in an upright position to allow patients to breathe more easily at night. Sublingual lorazepam for severe anxiety and dyspnoea and small doses of opiates to ease breathlessness in terminal stages may be used. [15]

 

Treatment:

Riluzole:

One of the drug riluzole (Rilutek) has been shown to slow significantly disease progression in humans. Riluzole is only neuroprotective agent licensed for use in MND. It is a sodium channel blocker. It inhibits glutamate release and primarily reduces excitotoxicity.

Though it has been revealed to have some other potentially neuroprotective effects. [16] In the UK, its use is recommended by the National Institute for Clinical Excellence (NICE) which estimated the cost of therapy to be £34000 to £43500 per quality-adjusted life year (QALY). [16] The NICE guidelines are:

 

·        Riluzole is recommended for the ALS form of MND

·        Therapy should be initiated by a neurologist, with routine supervision through locally agreed shared care protocols.

·        Dosage 50mg twice daily

·        Side Effects Nausea and vomiting,  Asthenia, somnolence Headache, dizziness, vertigo

·        Serious  Elevation in liver transaminases

·        Adverse Effects Regular monitoring of liver function is advised (every month for 3 months, every 3 months for a further nine months then annually thereafter)

·        Rare cases of neutropaenia have been reported White cell count must be checked in the case of febrile illness

·        Contraindications

·        Renal and hepatic impairment

·        Pregnancy and breast-feeding

·        Other symptomatic treatment is given in table no. 1

 


 

Table 1: Symptomatic treatment In Motor Neurone Disease [17, 18]

S.N.

SYMPTOMS

TREATMENT

1.

Muscle weakness and Tiredness

Physiotherapy to prevent muscle contraction and joint rigidity

·        Devices to retain mobility and independence such as ankle-foot orthoses, head supports, mobile arm supports, bathroom aids etc

·        Acetylcholinesterase inhibitors (pyridostigmine) can cause a short term improvement in fatigue in some patients

2.

Musculoskeletal Pain is common due to abnormal stresses on bones and joints

NSAIDs and physiotherapy are most effective

3.

Sialorrhoea (drooling) due to impaired swallowing and facial muscle weakness causes sore lips, dehydration, and embarrassment

·        Hyoscine transdermal patches, amitriptyline or atropine

·        Portable suction devices

·        Low dose parotid irradiation may be considered if drug treatment is not successful

·        B-blockers or carbocysteine reduce viscosity of secretions

4.

Pseudobulbar Affect : Inappropriate laughter or crying that often accompanies corticobulbar involvement

Responds well to amitriptyline or selective serotonin reuptake inhibitors (SSRIs)

5.

Psychological Problems: Depression and Anxiety

A grief reaction is a normal response to a devastating diagnosis. Clinical depression is also common and under diagnosed. It can be treated with tricyclic antidepressants or SSRIs.

6.

Sleep Disorders

Treatment should be directed at the cause of insomnia. Common causes in MND are respiratory insufficiency, anxiety, depression, muscle cramps, and inability to change position.

Use of sedatives should be avoided unless other options fail.

7.

Dysarthria

 

Simple strategies to improve communication can be taught by a speech therapist. When these become ineffective, a variety of communication aids are available, such as a light-writer

8.

·        Fasciculations,

·        Painful muscle cramps are common

·        Spasticity causes pain and decreased mobility

·         Anti-spasticity agents ( Baclofen, Tizanidine): Dose must be carefully titrated as loss of tone can worsen mobility

·        Quinine sulphate for cramps

·        Low-dose diazepam for cramps or fasciculations

9.

·        Constipation is common secondary to immobility,

·        Dehydration and weakness of abdominal muscles

·        Review medications (Analgesics and anticholinergics worsen constipation) and ensure adequate fluid intake

·        Bulk-forming or osmotic laxatives, glycerol suppositories

New potential neuroprotective agents evaluated for the treatment of motor neurone disease are given in table no. 2.

 

 

 

 

Table 2: New potential neuroprotective agents being evaluated in MND [19-2 1]

S.N.

Compound

Mechanism

Evidence

1.

Xaliproden

Oral neurotrophic agent

Neurotrophic effects in animal models of

neurodegeneration

2.

Minocycline

Inhibits activation of ca spases in the apoptosis cascade and microglial activation.

Prolonged survival in SOD1 transgenic mouse model of MND

3.

Celecoxib

A free radical scavenger and inhibitor of cyclooxygenase (COX). Marked increases in COX-2 have been found in MND spinal cord

4.

Co-enzyme Q10

A cofactor in the Q10 mitochondrial respiratory chain and endogenous anti-oxidant

5.

Ono-2506

An astrocyte modulator

Neuroprotective effects in cell culture and animal models of neuronal injury.

6.

Pentoxifylline

A phosphodiesterase inhibitor already used in the treatment of peripheral vascular disease

Identified as a potential therapeutic target for ALS through screening in transgenic mice

7.

Novartis TCH346

Anti-apoptotic agent currently undergoing clinical trial in MND.

 

 

 

 


Herbal treatment for Motor Neurone Disease:

Medicinal plants serve as therapeutic alternatives, safer choices, or in some cases, as the only effective treatment.

 

Ginseng-Korean:

The source of drug is main and lateral roots of Panax ginseng C. A. Meyer (Family- Araliaceae). ‘Gin’ refers to man and ‘seng’ to essence in Chinese, whereas ‘Panax’ is derived from the greek word, pan (all) and akos (cure) referring to its use as cure-all. Modern indications of this drug include low vitality, poor immunity and sexual function. [22]

 

Withenia:

The source of drug is primary roots of Withenia somnifera (Family- Solanaceae). It is commonly known as ashwagandha having Sanskrit meaning ‘horse like smell’. It is also known as Indian ginseng.

 

Several animal studies indicate the potential for protection of neurones. [23] In animal models of haloperidol- induced dyskinesia (chewing movements, tongue protrusion and buccal tremers) the reported benefits of Withenia appear to be due to its antioxidant rather than GABA- mimetic action. [24, 25] Invitro results suggest that withenolide A is able to reconstruct neuronal networks, including axons, dendrites, pre- and post synapses, in the neurons. [26, 27] Traditionally the drug is used in convalescence for people who are stressed and both physically and emotionally exhausted. It is considered a non-stimulating tonic allowing for restoration of vitality. [28, 29]

 

The drug may be used in dose of 5 -13 mL per day as fluid extract (1:2) or 3-6 g per day of dried roots in capsule or tea form. Large dose can cause gastrointestinal upset, diarrhea and vomiting, [30] central nervous system, respiratory depression and decreased body temperature. [31]

 

 

Nigella sativaL

Amongst potential medicinal plants, Nigella sativa is a wonderful herb with a wealthy historical and religious background. It is a dicotyledon plant belongs to Ranunculaceae family. [32] A number of pharmacological actions of N. sativa have been reported like hypotensive, anti-nociceptive, uricosuric, choleretic, anti-fertility, anti-diabetic and anti-histaminic. [33] One of the precious properties of N. sativa is the immunomodulatory effects of its constituents. Studies initiated more than a decade ago suggest that if it is used on a continuing basis, N. sativa can increase immune response in human being. The majority of subjects who treated with N. sativa oil for 4 weeks demonstrated a 55% increase in CD4 to CD8 T cells ratio, and a 30% increase in natural killer (NK) cell function. [34] Nigella sativa ameliorate age-associated decline in T cell functions. Nutritional supplementation can increase the immune response in elderly humans by altering both the total amount and the type of dietary lipids.[35] Nutritional supplementation with the Nigella sativa oil improves the immune response of healthy elderly subjects. It is mediated by a change in the factors closely associated with T cell activation. [36] In conventional and contemporary medicines numerous beneficial properties have been attributed to N. sativa and its chief constituent, thymoquinone (TQ). It should be revealed that TQ is seen to be the most useful known element of Nigella sativa which can be regarded as a valuable agent in the treatment of diseases of the nervous system. The results of some studies have shown that this plant can improve neurodegeneration, neurotoxicity, memory impairment, depression, epilepsy, anxiety and pain. [37]

 

Ayahuasca:

Ayahuasca is an Amazonian psychoactive preparation of two main components. Its active components are b-carboline and tryptamine derivatives. Ayahuasca use amongst the native people of the Amazon is a type of traditional medicine and cultural psychiatry. During the last two decades, the substance has become increasingly famous among both scientists and laymen. Currently its use is spreading all over in the Western world. Conventionally ayahuasca has been used in Ecuador, Columbia, Peru, and Brazil, where it is also known as natema, hoasca, daime, yagé, or yajé. The decoction is prepared by concurrently boiling two admixture plants, the Banisteriopsis caapi (Malpighiaceae) containing b-carboline type alkaloids for example harmine and tetrahydroharmine, and most commonly Psychotria viridis (Rubiaceae), which provides the psychoactive alkaloid dimethyltryptamine (DMT). [38, 39] The name ayahuasca is a compound word in Quechua language, where aya means soul, ancestors or dead persons and wasca (huasca) means vine or rope.[40]

 

ER (Endoplasmic Reticulum) stress with UPR (Unfolded-Protein Response) is thought to play a key role in neuropsychiatric illnesses such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, bipolar disorder, and in other illnesses of civilization such as atherosclerosis, diabetes, cancer, autoimmune, and cardiovascular disorders.[41]

 

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Received on 17.04.2018       Accepted on 30.05.2018     

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Ana. 2018; 8(2):117-122.

DOI:    10.5958/2231-5675.2018.00022.4