Cerebral ischemia: treatment with neurotrophic factors

K K Jain MD (Dr. Jain is a consultant in neurology and has no relevant financial relationships to disclose.)
Originally released November 24, 1997; last updated August 26, 2016; expires August 26, 2019

Overview

There is considerable evidence that neurotrophic factors are involved in the response to ischemic injury to the nervous system. This is the basis of investigation of neurotrophic factors–brain-derived neurotrophic factor, basic fibroblast growth factor, insulin-like growth factor-1, glial cell line-derived neurotrophic factor, and neuregulin-1–for therapy of stroke. Mechanisms of action are not fully understood but involve protection against neuronal damage, stimulation of neuronal sprouting, and promotion of synaptic reorganization. Experimental evidence is reviewed. Cell and gene therapy are used for delivery of neurotrophic factors to the brain.

Key points

 

• Neurotrophic factors are involved in response of the nervous system to injury.

 

• Several neurotrophic factors have been tested in clinical trials for the treatment of cerebral ischemia and most of these have failed in late stages.

 

• There are problems associated with delivery of neurotrophic factors to the brain.

 

• Administration of stem cells has been shown to increase the levels of neurotrophic factors and is associated with improvement in neurologic deficits resulting from cerebral ischemia.

Historical note and terminology

A trophic factor can be generally defined as any molecule that supports the survival of neurons. Nerve growth factors are polypeptides that regulate the proliferation, survival, migration, and differentiation of cells in the nervous system. Most studies have focused on the effect of growth factors on neuronal survival and maintenance, hence the term “neurotrophic factors.” By definition, a neurotrophic factor is synthesized by, and released from, target cells of the neurons, bound to specific receptors, then internalized and transported by retrograde axonal transport to the cell soma where multiple survival-promoting effects are initiated.

Growth factors termed “cytokines” have also been found to modulate neuronal processes. Originally, cytokines were considered to be derived solely from the cells of the immune system, but now, they are known to be produced by the cells of the central nervous system also. In this article, the term “neurotrophic factors” will be used in a broad sense to cover neurotrophins, nerve growth factor, and other substances that promote survival and repair of the cells of the nervous system. The term “angioneurines” covers vascular endothelial growth factor, neurotrophins such as brain-derived neurotrophic factor, insulin-like growth factor I, and erythropoietin, which affect both neural and vascular processes that are important in recovery and regeneration following stroke (Lafuente et al 2012).

The current management of ischemic stroke is unsatisfactory. Acute management of cerebral infarction consists primarily of thrombolytic therapy to undo the effects of vascular occlusion. This has to be carried out within a narrow therapeutic window and has the potential complication of intracerebral hemorrhage. No proven effective agents are available for limiting or reversing cerebral infarction, and there is an urgent need for developing new drugs for this purpose.

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