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sensory neuron and motor neuron. Sensory neuron brings the signal from the target organ to brain in the form of electrical impulses and motor neuron has just the opposite function i.e. it brings the impulses from brain to target organ to respond against the particular stimulus. In MND these motor neurons are get affected that control voluntary muscle including speaking, walking, breathing, sawalloing and general movement of body. Skeletal muscle are innervated by a group of neurons (lower motor neuron) located in the ventral horn of spinal cord which projectout the ventral roots to the muscle cells. These nerve are innervated by corticospinal tract or upper motor neuron that project from motor cortex of brain. In microscopic pathology there is degeneration of ventral horn of spinal cord as well as atrophy of ventral roots.
Motor neuron disease (MND) are the group of neurological disorder. It affects the motor neurons. Motor neurons have main function in bringing the signal in form of impulses from brain to the effectors organs (target organ) and in this way control the voluntary activity like walking, speaking, swallowing and other general movements.
A French neurologist, Jean Martin Charcot, first suggested club together all conditions that affect the lateral horn of spinal cord in 1869. The other common name for MND are- ALS (amyotrophic lateral sclerosis), primary lateral sclerosis (PLS), progressive muscular atrophy (PLS).
The cause of MND is sporadic. Genetic factor and environmental factor are responsible for it up to some extent. The motor system mainly consist of four parts: pyramidal system, basal ganglia, cerebellum and neuromuscular system. The lesion in any of them can lead to neurodegenerative disease. There may be several reason associated with lesion like intracellular hemorrhage, stroke etc.
There is not much scope available for treatment of this disease permanently. Medical science still does not have any effective and permanent cure. Here I am trying to use stem cell technology approach for the treatment of this disease. As stem cells are the master cells of human body and can have capacity to derive all kind of cells. Because of its versatile nature, these cell can generate the motor neuron cells which get degenerated in MND. Here some stem cells cell approach is being consider and technique involved for its treatment are neural stem cell approach, the delivery of stem cells into multiple site and affected area, induced pluripotent cells approach, glial restricted precursor approach, cell therapy approach etc.
The motor system:
The motor system consist of:
Pyramidal system (upper motor neuron)
The basal ganglia (extrapyramidal system)
The normal motor pathway contain upper motor neuron that synapse in the brainstem and spinal cord with lower motor neuron. The nerve cell bodies of of upper motor neuron (UMNs) lie in the precentral gyrus of the cerebral cortex and in several brainstem nuclei, their axon synapse with motor nuclei in brainstem (cranial nerve nuclei) and the spinal cord (peripheral nerve). Lower motor neuron (LMNs) have their cell bodies in the anterior horn (AHC); their axon transmit impulse through their anterior root into peripheral nerve terminating at neuromascular [junction Rosa-Eva Huettl et al, Feb 2011].
Skeletal cells which are voluntary in nature are innervated by group of neurons (LMNs) which are located in the ventral horn of spinal cord and these nerve cells are innervated by corticospinal tract(UMN) which project from motor cortex of brain.
Three kinds of motor pathways impringe on the anterior horn cells ; the corticospinal tract, the basal ganglia system, and the cerebellar system. These are additional pathway originating in brainstem that mediate flexor and extensor tone in limb movement and posture most notable in coma. All these higher motor pathways affect movement through the LMNs- so called the “final common pathway”.
Fig 1: representation of motor cortex and internal capsule. The principal motor pathway (pyramidal tract) is depicated.
The movement whether initiated voluntarily in the cortex, “automatically” in the basal ganglia or reflexly in the sensory receptors, must ultimately be translated into action via anterior horn cells. A lesion in any of the above mentioned area will affect movement or reflex activity.
The three principal motor pathway are:
The corticospinal (pyramidal) tract: the cortiocospinal (pyramidal) tracts mediate voluntary movement and integrate skilled, complicated, or delicate movement of selected muscular actions and inhibit others. They also carry impulses that inhibit tone, hence, their lesion results in hypertonia.
The corticospinal fibres originate in the cerebral cortex (precentral mortex cortex) pass through corona radiata and condense in the internal capsule, pass through its posterior limb and travel own through mid brain, pons and comes down into lower medulla, where they form an anatomical structure resembling a pyramid. There most of the fibres cross to the opposite or contralateral side of the medualla, pass downwards and synapse with the anterior horn cells or with internuncial neurons. Tracts synapsing in the brainstem with motor nuclei of the cranial nerves are termed corticobullar fibres (tract).
The basal ganglia system: it included motor pathways between the cerebral cortex, basal ganglia, brain stem and spinal cord. It controls tone, posture and body movement especially gross “automatic” movement such as walking.
The cerebellum: it receives both sensory and motor inputs and controls the co-ordinates the motor activity, maintains equilibrium and control posture.
Body part representation in motor cortex and internal capsule:
The body part are represented in contraleteral hemisphere in a characteristic fashion i.e. lower limb occupies upper position, face occupied lower most, arm and trunk occupy a large area. Similarly, the parts of the body capable of performing delicate movements have largest cortical representation.
In internal capsule, the representation of the part is reserved. The upper limbs, trunk and lower limbs occupy upper middle and lower parts of posterior limb of the internal capsule.
Change in the posture and alteration in the tone of many muscles requires for the movement of body. Some quite distant from the part being moved. The motor system consist of hierarchy of control mechanism that maintain body posture, baseline, muscle tone upon which a specific movement is superimposed. The lowest order of the hierarchy lies in the gray matter of spinal cord which control the muscle tone in response to stretch and the reflex withdrawl to noxious stimuli.
Above the spinal cord, circuits between basal ganglia and motor cortex constitute the extrapyramidal system which control background muscle tone and body posture and gate the initiation of movement.
Cause of MND and symptoms associated with it:
Almost 90% of MND cases are “sporadic” [Leyanx Xu et al, April 2009] i.e. the patient have not family record of this disease. Genetic factors and environmental factor is important in determing individuals sucettibility. Some genes linked to ALS are: Cu/Zn superoxide dismutase SOD1, ALS2, NEFH, SETX and vesicle associated with protein B (VAPB).
SOD1 mutation is responsible for about 20% of the MND case among in a family. The main product of SOD1 gene is superoxide dismutase enzyme. It act as a free radical scavenger and function as to reduce the oxidative stress of cells throughout body [Gurney ME et al, April 1997] . Till now about more than 100 different kinds of mutation in SOD1 gene have been found, which account for development of MND and its some other forms as well (ALSOD database).
AV4 is the most commonly mutation occurring in North America and occur in up to 50% of SOD1 cases. In such a way different region and countries have different mutation which directly or indirectly affect SOD1 gene. For instance, in Japan the most common mutation is H46R. D90A mutation is associated with the slow progression of ALS is found in the people of Scandinavian [Gurney ME et al, April 1997]. As SOD1 gene is involved in the reduction of oxidative stress so its mutation confers a gain in toxic and affect the nerve cells.
Rather than this aspect lesion in various parts of the motor system produce distructive pattern of motor deficit. These can induce negative symptoms of weakness, lack of coordination, lack of stability and stiffness or positive symptoms such as tremor, dystonia, chorea, athetosis, hemiballism, tics and myoclonus. When the lower limbs are affected, characteristic pattern of gait disorder may result.
Lower motor neuron lesion:
It consist of anterior horn cells, nerve roots, peripheral nerves and myoneural junctions. Groups of muscle fibres innervated by single anterior horn cells (LMN) from a motor unit, hence, it will cause loss of function of these motor unit and muscle fibres innervated by them result into weakness, flaccid, paralysis, atrophy and wasting the muscles and these muscle fibres depolorise spontaneously producing fibrillation.
Sign and symptoms of lower neuron lesion:
Weakness or loss of movement.
Decrease tone (hypotonia-flaccid paralysis).
Loss of tendon and superficial reflexes.
Wasting of muscle leading to atrophy.
Trophic change in skin and nail in neutropathies.
Contractures of muscle.
Upper motor neuron lesions:
The corticospinal tract (UMM) extended from the cortex to spinal cord, when damaged or destroyed, its function are reduced or lost below the level of lesion.
When UMNs are damaged above the crossover of tract in medulla, motor impairment develops on opposite or contralateral side.
In damage below the crossover, motor impairment occur on same or ipsilateral side of body.
A UMN lesion manifests clinically:
Weakness of limb or limbs.
Brisk tendon stretch reflexes and loss of superficial reflexs.
Hypertonia i.e. spastic increase in tone greater in the extensors of lower limb and flexors of upper limb which is a characteristic pattern of hemiplegia.
Extensor plantar responses.
The weakness is more pronounced in extensors of upper limbs and flexors of lower limb.
Little or no wasting of muscles.
Extrapyramidal lesions: Disease of basal ganglia or extrapyramidal system does not cause paralysis but produce an increase in tone, disturbance in posture and gait, a slowness or lack of spontaneous and automatic movement termed bradykinesia, and a variety of involuntary movements.
Cerebellar lesions: it leads to:
Lack of coordination on the same side of body. The initial part of movement is normal but as target is approached and accuracy of movement deteriorates resulting in intention termor.
Impairment of gait, equilibrium and postures. Lesions involving the cerebellar hemisphere lead to ataxic gait; while involvement of central vermis leads to truncal ataxia (patient has difficulty in sitting up, or standing).
Decrease in muscle tone due to involvement of red nucleus.
Paralysis is not a feature of cerebellar disease.
Except all these “stroke” is also one of the commonest cause for motor neuron disorder.
Clinical diagnosis established by neurologist on the basis of neurological examination. Investigation such as blood test, EMG (electromyography), MRI (magnetic resonance image) and sometime genetic testing to diagnose the disease. The other way to diagnose the disease is by concentrating on symptoms and body condition.
Riluzole is the only drug that affect the course of disease [Theiss RD, et al, mar 2011]. This drug function by blocking the effect of neurotransmitter glutamine and is extend the life spain of an an ALS patient by only few months. Still there is no total cure of MND. The other treatment is being used are acute stroke management, as stroke is one of commonest cause of development of this disease.
Stem cell approach for treatment of motor neuron disease:
As mention above the main cause of this disease is degeneration of motor neurons. So application of stem cell technology in the generation of motor neuron can be very useful technique to treat this disease. Stem cells are the master cells of the human body. Because of versatile nature, stem cells have potential to repair or replace the degenerated cells.
There are many issue which are important to be consider if we translate the current knowledge of stem cell into the treatment of neurodegenerative disease. First of all the clinically competitive and risk to the patient acceptable is necessary to be define. One of the important issue is that the proliferation and differentiation are difficult to control. Animal model may not fully predict their toxicity and risk involve for development of tumor formation after implantation [ Olle lindvall et al,4 jan 2010].
The disease pathology has to be determine that which cell be generating from stem cells. Different cells will be needed for different disease in replacement therapy.
Prior to the clinical application, it must be demonstrated in animal model that stem cell based approach induce substantial improvement of function deficits that resemble the debilitating symptoms in patient.
It is also important to determine biological mechanism involved the observed effect of stem cell treatment in animal model.
Motor neuron cell has been developed invitro from different stem cells sources including mouse and human stem cells [Roy et al, year 2005]. Neural stem cells (NSCs) has been derived from fetal rat spinal cord [Lee H, et al. year 2007] and human forebrain and some other cells like iPS cells. These stem cell derived motor neuron precursors and neuroblast inviro. The motor neuron have extended axon to ventral roots. After transplanting into spinal cord of adult rabbit having the motor degeneration problem, form the neuromascular junction and it give rise to partial recovery from paralysis. after transplantation into the affected area of adult mice and maturation, the stem cells derived motor neuron and attend muscular atrophy.
Fig 2 : stem cell based therapeutic approach for motor neuron disease (ALS). ALS leads to degeneration of motor neuron in the cerebral cortex, brainstem, and spinal cord. The stem cell based approach can be induce neuroprotector or dampen detrimental inflammation by implanting stem releasing growth hormone. Finally stem cells derived spinal motor neuron precursor or neuroblast could be transplanted into damaged area to replace damaged or dead neurons. [ Olle lindvall et al,4 jan 2010]
Still this approach has not been successful totally to cure MND in case of human. There a several experiment hurdle which must have to overcome so that the cell replacement therapy to become successful. To achieve this goal we must know the specificity of the cell target, homing and special markers. The stem cell must be delivered at multiple site along the spinal cord . the upper motor neuron formed must be innervates to the lower motor neurons the other important aspect is that differential of spinal motor neurons can be directed to the correct cervical, thoracis or lumber phenotype and finally cell project at axial or limb muscles .
The central motor neuron like corticospinal neuron also can be replaced which gate degenerated in motor neuron disease. The life Spain of new motor neuron generated should be appropriate. It should also be determine weather the environment in the spinal cord of patient with ALS, which hostile to motor neuron, can be altered [ Olle lindvall et al,4 jan 2010].
The genetical factor is one of the important factor to be consider. The person having ALS carrying genetic mutation in the glial cell so modification of the microglial cell or astrocyte for long term survival of transplanted motor neuron. Stem cell transplantation to counteract motor neuron loss by releasing neurotrophic molecules or modifying the inflammatory environment, play a major role in disease progression. It is more near term clinical goal for ALS [ Olle lindvall et al,4 jan 2010].
Induced pluripotent stem (iPS) cells approach:
Induced pluripotent stem (iPS) cell as indicated above in the previous section, can be one of the important approach to treat motor neuron disease. These iPS cells are derived from epigenetic reprogramming of somatic cells through the exogenous expression of transcription factor. These iPS cells are also having the characteristic property like to that of embryonic stem cells and hence can have the major impact on disease like neurodegenerative disorder and regenerative medicine. These iPS cells are also self renew and retain potential to be differentiated into all cell type of body [Evangelos kiskins et al]. The another approach to treat MND is directed differentiation of human induced pluripotent (iPS) cell to functional neural phenotype is unknown. Human embryonic stem cells, specified to neural lineage, this cell could be differentiated to form motor neuron with similar efficiency [S karumbayaram et al, July 2010].
Spinal muscular atrophy (SMA) is also one of the common type of neurological disorder leading to infant mortality. This cause selective loss of lower motor neurons which finally result into muscle weakness, paralysis and often death. In this iPS cells were used. iPS cells were taken from skin fibroblast from the child with SMA. These cells expanded robustly in culture, maintained the disease genotype and generate motor neuron that showed selective deficits compared to those derived from child’s unaffected mother. This was very essential in many other aspects like it can be used to model the specific pathology seen in a genetically inherited disease, study disease mechanism, screen drug compounds and develop new therapies [Allison D Elbert et al, 15 jan 2009]. Recently human neural stem cells (NSC) graft ameliorate MND in SOD1 transgenic model [Leyan Xu et al, April 2009].
One of the important stem cell approach for treatment of MND is that stem cells derived motor neuron may not survive when exposed to the harsh microenvironment in spinal cord of ALS. Rather than this stem cell may be used for studying glia- mediated toxic mechanism and other therapies in ALS [Jason R Thonhoff et al, June 2008].
Cell therapy may be a promising new treatment for MND. Recently it has been shown a single low dose (106 cells) of mononuclear human umbical cord blood cells administrating intravenously to mice delayed symptoms progression and modestly prolong life span [Svitana Garbuzova Davis et al, 17 June 2010].
Motor neuron disease is due to degeneration of motor neurons. The reason associated with it may be several like genetic factor, environmental factor etc. lesion in the parts of motor system is also one of the important cause of motor neuron disease. Although still there is no permanent cure of this disease. Medical science is concentrating on controlling the factors which are responsible for account of this disease to cure this disease like stroke is one of the common cause for MND so medical science is concentrating to overcome this stroke. Except this, medical science is also concentrating on lesion cure this disease. The main problem with medical science is that it is unable to activate the degenerated cell. Once the cell is dead or degenerate is impossible to make active. The only possible way is replacement of those degenerative and dead cells.
Studies are being done to replicate the function of the neuron in term of MEMS (microelectromechanicalsystem) which can be used to replicate the degenerated neurons with these MEMS based microdevices.
Apart from all these aspect according to me, stem cell technology approach is the best way to cure this disease. Because the cell which gets degenerated are being replaced here by the new cells produced by stem cells. So the biological environment is being maintained and the normal physiology can be retained by development of same cells which gets degenerated. Still this approach is not being successful because of the experimental hurdle. There is need of more study specially in specificity of the cell target, homing and special markers so that the transplantation is appropriate and it produce the degenerated cells. The various clinical trials are in progress in USA and hopefully as in other animal models it will be also work on human.
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