[HTML][HTML] Neurodegeneration and neuroprotection in glaucoma: development of a therapeutic neuroprotective vaccine: the Friedenwald lecture

M Schwartz - Investigative ophthalmology & visual science, 2003 - iovs.arvojournals.org
Investigative ophthalmology & visual science, 2003iovs.arvojournals.org
Injury to the central nervous system (CNS) causes irreversible functional loss, as there is
little or no neurogenesis (because adult neurons cannot proliferate and repopulate the site
of injury), little or no regeneration (because neurons with axonal damage have limited
capacity for spontaneous regrowth), and ongoing secondary degeneration (because the
primary neuronal loss creates an environment hostile to neurons that escaped direct injury,
causing them to degenerate). Research in my laboratory over the past two decades has …
Injury to the central nervous system (CNS) causes irreversible functional loss, as there is little or no neurogenesis (because adult neurons cannot proliferate and repopulate the site of injury), little or no regeneration (because neurons with axonal damage have limited capacity for spontaneous regrowth), and ongoing secondary degeneration (because the primary neuronal loss creates an environment hostile to neurons that escaped direct injury, causing them to degenerate). Research in my laboratory over the past two decades has been aimed at finding ways to promote the recovery of damaged nerve fibers. In the course of these studies, it became clear that only part of the functional loss after an injury is due to neuronal losses caused by primary transection of nerve fibers and for which the appropriate therapy would be nerve regeneration. A significant part—and sometimes the major part—of the loss of function is due to delayed degeneration of fibers that escaped the primary injury. This secondary loss is a consequence of numerous injury-related processes, which were found to be common to many acute and chronic neurodegenerative disorders (Fig. 1). The appropriate therapy for preventing or minimizing the degeneration of neurons that escaped direct injury is neuroprotection. Neuroprotective therapy is a general term referring to any therapeutic approach that neutralizes, circumvents, and prevents neuronal losses caused by self-destructive processes. Our research focuses on achieving recovery by both neuroprotection and neuroregeneration. The devastating processes triggered by the injury affect and are affected by events associated with cells that support the neurons, and not only with the neurons themselves. Thus, for example, if astrocytes die or malfunction as a result of the primary injury, the normal capacity of the neuronal environment to buffer neurotoxic agents is reduced or destroyed. This contributes to an increase in toxicity and further affects both neurons and astrocytes, leading to their death (Fig. 2). Research groups in many parts of the world have been seeking ways to stop or at least slow down the process of damage propagation as a therapeutic strategy after acute nerve injury. Recently, it became clear that such neuroprotective therapies would also be applicable to chronic neurodegenerative disorders. Common strategies include pharmacological intervention (for example by glutamate-receptor antagonists, 2-adrenoreceptor agonists, Ca2 blockers, scavengers of free radicals) and molecular intervention (for example, the use of anti-apoptotic or survival genes to increase neuronal resistance to injurious conditions).
The neuroprotective strategy developed by my research group, and presented in this lecture, is based on the assumption (borne out by experimental evidence) that the body harnesses the immune system to help cope with the stressful conditions imposed by an injury. In practical terms, this requires reinforcement of the immune response by boosting the body’s own mechanisms of defense and repair, while avoiding the risk of autoimmune disease.
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