NEURAL REPAIR : NEW HOPES AND ACHIEVEMENTS

In the past fifty years, medicine made impressive progress in the repair of nerves of the PNS. However, no achievement so far could restore damages in the CNS. Recent discoveries may change this scenario and shed new light on the treatment of neurodegenerative diseases and injuries in the spinal cord.



Human Nervous System
The human nervous system is composed of a Central Nervous System (CNS) and a Peripheral Nervous System (PNS). The spinal cord and brain compose the CNS, whereas the PNS is basically consisting of nerves.



Nerves are similar to an electrical wiring that transmits information between the brain and the body through electrical signals (nerve impulses). Nerves are composed of several fibers, axons. Axons are long and slender regions of the nerve cell (neuron). Nerve fibers are grouped in fascicles, surrounded by connective tissue and covered by a tissue ring (epineurium).

Peripheral nerves comprise motor and sensory nerves; the first transmit movement signals from the brain and spinal cord to the muscles and control voluntary movement, whereas the latter send sensory information, such as pressure, and temperature from the body to the spinal cord and brain.

Nerve Repair

Nerve Damage and Repair
When nerves break, the transmission of nerve impulses is interrupted, and a process of regeneration and degeneration starts. In case nerve severance is not complete, i.e., the damage is restricted to the fiber and the cover and insulation tissue is intact, the end of the fiber closest to the brain regenerates until reaching a sensory receptor or muscle, but the end farthest to the brain dies. However, if the damage affects fiber and insulation, the nerve is not properly fixed and requires surgical intervention.

Available Treatments For Nerve Repair
The treatment of soldiers wounded in war allowed a remarkable progress in nerve repair. Those advances made possible today’s microsurgeries and transplant of nerves. More recently, the use of absorbable neuro tubes and fibrin glue enhanced healing and decrease sequelae.

Neurotrophic Factors: Body’s Healing Proteins
Nerve regeneration in humans varies from 1-2 mm/day and is triggered by neurotrophic factors. Neurotrophic factors are large proteins naturally produced by the body involved in the proliferation and differentiation of different cell types. They promote survival of neurons and growth of axons after damage.

The study of neurotrophic factors started in the 1950s with the discovery of the Nerve Growth Factor (NGF), followed by the findings of the brain-derived neurotrophic factor (BDNF) in the 1980s, and Neurotrophins 3 (NT-3) and 4/5 (NT-4 or NT-5) in the 1990s. Since then, scientists discovered other neurotrophins and made in vitro, in vivo, and clinical tests to understand their effects.

Each neurotrophic factor has a different function and acts on a particular group of neurons, but all contribute to the survival and regeneration of neurons. The therapeutic use of two or more neurotrophic factors seems to have a synergic effect on nerve regeneration, in particular when associated with absorbable biomaterials able to control their releases, such as neuro tubes and fibrin glue.

Besides the use in the peripheral nerve system (PNS) for nerve repair, neurotrophic factors have also a potential use in the central nervous system (CNS), where neurons have more difficulty to fix themselves. They could represent a promising tool to heal spinal cord injuries and neurodegenerative diseases, such as Alzheimer and Parkinson, which have been considered irreversible so far.

However, there are some problems involving the clinical use of neurotrophic factors: poor oral availability, low serum stability, and inefficient penetration in the nervous system, as they cannot cross the blood-brain barrier due to their large size.

Small Molecules with Neurotrophic Properties
As an alternative for those drawbacks, scientists from Japan propose the use small molecules with neurotrophic properties. According to them, molecules present in the extract of some plants (e.g.: Magnolia ovobata, Zingiber purpureum, Illicium sp.) can mimic properties of neurotrophic factors by directly activating or up-regulating neurotrophic receptors. Those molecules also enhance neurotrophic signaling pathway and avoid neuron death. As those natural products are rare, scientists recommend their synthesis to enable clinical tests.

Synthesized Neurotrophic Agents: New Hopes For Old Diseases.
Luckily, science progressed fast. Last January, scientists from the Department of Chemistry of the Dartmouth College, New Hampshire, USA announced they produced chemical reactions that resulted in the synthesis of rare small molecules with potent neurotrophic effect. This accomplishment opens several doors for research not only to improve the techniques used to repair peripheral nerves but also in the treatment of degenerative brain diseases and spinal cord injuries.

Suggestions for further reading:
Akagi, M., Matsui, N., Akae, H., Hirashima, N., Fukuishi, N., Fukuyama, Y. and Akagi, R., 2015. Nonpeptide neurotrophic agents useful in the treatment of neurodegenerative diseases such as Alzheimer’s disease. Journal of pharmacological sciences, 127(2), pp.155-163.
Sebben, A.D., Cocolichio, F., Schmitt, A.P., Curra, M.D., Viegas, P., Tres, G.L. and Silva, J.L.B., 2011. Effect of neurotrophic factors on peripheral nerve repair [Abstract in English, text in Portuguese]. Scientia Medica, 21(2), pp.81-89.
Cheng, X. and Micalizio, G.C., 2016. Synthesis of Neurotrophic Seco-prezizaane Sesquiterpenes (1R, 10S)-2-oxo-3, 4-dehydroneomajucin,(2S)-hydroxy-3, 4-dehydroneomajucin, and (–)-jiadifenin. Journal of the American Chemical Society.

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