Summary: Tissue and organ regeneration is a very precious property. Skin that heals after an injury, bones that mend following a fracture are both natural phenomena. However, when a bone marrow injury occurs, it can mean life long paralysis for the injured person. The central nervous system (CNS), brain and bone marrow, unlike other tissues of the body, do not produce spare cells. There is nonetheless hope, since growth factors linked to the regeneration mechanism of nerves have been identified through research.
Central Nervous System and Neurotrophic Factors
All our vital activities take place in the central nervous system (CNS). It is constituted of the brain, cerebellum, bone marrow, and brain stem. From it, a whole network of bundles, the peripheral nervous system (PNS), innervates the various parts of the body.
The neuron (or nerve cell) is the basic unit of these systems. It is responsible for receiving and transmitting sensitive and motor data to the whole body. It contains, within its center, a cellular body that reaches on either sides with short and ramified processes called dendrites, as well as one main process called axon. The dendrites receive data incoming from other neurons (fig.1) The axon's role is to direct the nervous impulse toward a synapse, contact zone between two neurons or between a neuron and a cell of a different type, such as a motor end=plate of a muscle. The axons gather into bundles to form nerves.
The axon's structure is different depending on it's localization: the CNS or PNS. In the CNS, it is surrounded by a myelin sheath formed by oligodendrocytes, while in the PNS the myelin sheath is produced by Schwann cells. A neuron also produces neurotransmitters, such as acettylcholine and catecholamines, which define if it is a cholinergic or adrenergic neuron.
The brain, as soon as it takes shape during embryonic life, disposes of some 200 billion neurons. This number decreases to approximately 100 billion at birth, and remains constant until age 40. Later, the number decreases irreversibly with a daily loss of 10 thousand neurons per day. This phenomenon is associated with a gradual decline of the sensory, motor and cognitive capacities.
A lost neuron is never replaced. In adults, there are no undifferentiated cells that could become a neuron. We thus have a neuronal capital that cannot be increased. On the other hand, if the axon is the only one touched,the neuron can either die, atrophy, or regenerate its axon. This regeneration is however only possible in the PNS, since Schann cells are able to induce the production of growth factors (or neurotrophic factors). Neurons of the CNS cannot benefit from such a phenomenon, not because of their own nature but because of their environment. Some researchers have identified protein located on the oligodenrocytes surface which prevent axon growth by causing its retraction. This phenomenon has also been observed with mechanical lesions where astrocytes multiply, and replace the injured axon as it degenerates. However if the CNS is given the necessary substrate, in this case neurotrophic factors, that it cannot produce itself, it will be able to survive and to regenerate in case of lesions.
Growth factors that allow neurons to regenerate their axon are also called neurotrophic factors (fig.2) NGF (Nerve Growth Factor) is the most widely known. Recently, other factors have been identified, such as BDNF (Brain Derived Neurotrophic Factor), CNTF (Ciliary Neurotrophic Factor), GDNF (Glial Cell-line Neurotrophic Factor), and IGF (Insulin Growth factor), to name only a few.
There is a correlation between a tissue's capacity to produce NGF and the number of sympathetic and sensitive nerves it contains. NGF is synthesised by Schann cells and fibroblasts. It is also found in the cerebral cortex and hippocampus. BDNF is found in the hippocampus, cortex, cerebellum, diencephalon, and mesencephalon.
In the PNS, neurotrophic factors bind to receptors located on the surface of nerves, and transport to the cell body where they play their trophic role. Thus, if a nerve is severed, the neuronal cellular body is deprived of the axonal ending that provides the NGF required for its growth. Schann cells will then start producing NGF, but very often only compensate for the lack of growth factors and allow a quicker regeneration. The therapeutic effect of exogenous neurotrophic factors lets us hope for results with certain neurodegenerative or neuromuscular diseases.
Parkinson's disease is one of the neurodegenerative diseases that leads to motor disorders. It is caused by a degeneration of the brain stem's nerves, in the black substance, neurons that usually innervate a motor structure located under the cortex where they release dopamine. Recent studies have shown a specific effect of certain factors such as BDNF and GDNF, which would allow survival and differentiation of adrenergic cells. If their effects are confirmed through animal studies, these factors will become the treatment of choice against Parkinson's disease.
Administration of these factors is however limited, since they cannot cross the hematoencephalic barrier.
Neuromuscular diseases are characterized by the death of the motor neurons that link the bone marrow and motor end-plate. It is the case with anyotrophic lateral sclerosis (ALS). Several researchers think that the death of these neurons could result from the non availability of neurotrophic substances.
Recent studies have shown that concomitant administration (in vitro, and in Wobbler mice) of CNTF and BDNF helped increase the muscular mass, and delayed neuronal loss. Other factors, such as GDNF and IGF, also seem promising.
Certain antineoplastic agents used in chemotherapy, such as vincristine, cisplatine, and taxol, cause adverse effects, despite their efficiency. Neurotoxicity is one effect that causes neuropathies such as paresthesia, numbness of the tips of the fingers and toes, and neuritic pains that can lead to often irreversible motor disorders.
The efficiency of neurotrophic factors, such as NGF and IGFm has already been shown in mice that had recieved antineoplastic agents: they favilitate the budding of nerve fibers, which seems to restore the neuromuscular functions that were diminished by chemotherapy.
Because of the discovery of neurotrophic factors, it is now incorrect to think that nerve cells lesions are irreversible. These factors make it possible to improve the regeneration of injured nerves of the PNS and CNS. The therapeutic effect of neurotrophic factors is extremely promising. Research will probably make it possible to develop treatments for so-called incurable diseases using combinations of such factors. The CNS and lungs of bovine embryos are naturally rich sources of neurotrophic factors.
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Neurotransmitter: substance that transmits nerve impilses across a synapse.
Exogenous: factor or agent from outside the organism or system.
Hematoencephalic Barrier: barrier made of the internal membrane of the capillaries of the CNS that prevents certain molecules crossing from the blood into the cereral tissues.
Antineoplastic: inhibiting or preventing the growth and spread of neoplasm or malignant cells.
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