Natcell CNS Targets the Effected Area of Your Central Nervous System

CNS Integrins Switch Growth Factor Signaling to Promote Target-Dependent Survival.
Department of Medical Genetics and Center for Brain Repair,
University of Cambridge, Cambridge CB2 2PY, UK.

Depending on the stage of development, a growth factor can mediate cell proliferation, survival or differentiation. The interaction of cell-surface integrins with extracellular matrix ligands can regulate growth factor responses and thus may influence the effect mediated by the growth factor.

Here we show, by using mice lacking the alpha(6) integrin receptor for laminins, that myelin-forming oligodendrocytes activate an integrin-regulated switch in survival signalling when they contact axonal laminins. This switch alters survival signalling mediated by neuregulin from dependence on the phosphatidylinositol-3-OH kinase (PI(3)K) pathway to dependence on the mitogen-activated kinase pathway. The consequent enhanced survival provides a mechanism for target-dependent selection during development of the central nervous system. This integrin-regulated switch reverses the capacity of neuregulin to inhibit the differentiation of precursors, thereby explaining how neuregulin subsequently promotes differentiation and survival in myelinating oligodendrocytes.

Our results provide a general mechanism by which growth factors can exert apparently contradictory effects at different stages of development in individual cell lineages.

SOURCE

Nerve Regeneration
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.

Neurotrophic Factors
Growth factors that allow neurons to regenerate their axon are also called neurotrophic factors 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 synthesized 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.

Neurodegenerative 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
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.

Neuromuscular Neuropathies
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 received antineoplastic agents: they favilitate the budding of nerve fibers, which seems to restore the neuromuscular functions that were diminished by chemotherapy.

Conclusion
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.

References
Apfel S.C., J.C. Arezzo, L.A. Lipson, J.A. Kessler.
Nerve growth fator prevents experimental cisplatin neuropathy. Annals of neurology. (1992). 31:65-80

Campenot R.B.
Nerve and the local control of nerve terminal growth. Journal of neurobiology. (1994). 25:599-611

Di Numzio C.M. Sciences et Vie. (1995) 928:40-46

Fusco M., F. Vantini, N. Schiavo, A. Zanotti, R. Zanoni, L. Facci and S.D. Skaper.
Gangliosides and neurotrophic factor in neurodegenerative diseases: from experimental finding to clinical perspectives.

Guyon C. Maladies neuromusculaires. La recherche. (1995) 26:86-187

Hammond C., D. Tritsh. Neurobiologie Cellulaire. Douin. (1990)

Henderson C. E., H.S. Phillips, R.A.Pollock, A.M. Davis, C. Lameulle, M. Armanini, L.C. Simpson, B. Moffet, R.A. Vandlen, V.E. Koliatsos, A. Rosental.
GDNF: a potent survival factor for motomeurons present in peripheral nerve and muscle. Science. (1994) 266:062-1064

Koning P.N.M., W.K. Makking, A.M.L. VanDelft, G.S.F. Ruigt
Reversal by NGF of cytostatic drug-induced reduction of neurite outgrowth in rat dorsal root ganglia in vitro. Brian Research. (1994) 640:195-204

Lewis M.E., J.L. Vaught, N.T. Neff, P.E. Grebow, K.V. Callison, E. Yu, P.C. Contreras, F. Baldino Jr.
The potential of insulin-linke growth factor-1 as a therapeutic for treatment of neuromuscular disorders. Ann. N.Y. Acad. Sci. (1993) 692:201-208

Saffran B.N. Should intracerebroventricular nerve growth factor be used to treat Alzheimers disease? Perspective in biology and medicine. (1992) 35:471-486

Schnell L., M.E. Shwab. Axonal regeneration in the rat spinal cord produced by an antibody against myelin associated neurite growth inhibitors. Nature. (1990) 343:269-272

Glossary
Neurotransmitter: substance that transmits nerve impulses 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.