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Central nervous system injury and neurological diseases are recognized as an increasing health and social problem in America and throughout the world, one that can be expected to grow in numbers and cost as the population ages.

According to the Centers for Disease Control and Prevention, stroke is the third leading cause of death in the United States and the primary cause of disabilities in adults. Throughout the country, strokes occur at the rate of one per minute. More than 700,000 Americans experience a stroke each year and more than 157,000 of those will die. The estimated cost of stroke to the nation each year is 57.9 billion dollars.

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Fig. 1 Parkinson’s Disease (illustration)
Fig. 2 Fluorescence photomontage
Fig. 3 Chronic Stroke (illustration)
Fig. 4 Sagittal (side view) of the brain and head (illustration)

Cross section of the brain illustrating how TGFα acts to repair damage in the brain of patients (and animal models) with Parkinson’s disease.

At the right are the key brain structures involved, including the striatum, the pallidum, the thalamus, and the midbrain dopamine neurons of the substantia nigra-ventral tegmental area. At left the cortical-striatal pallidal-nigral-thalamic-cortical “loop” is shown. In PD, the dopamine neurons degenerate and thus their connection to the striatal neurons is lost. TGFα infused into the striatum, or intranasally, induces the adult stem cells lining the ependymal and subventricular zone adjacent to the striatum to divide (proliferation) in great numbers (hundreds of thousands to millions of new progenitors). They then migrate to the regions of the striatum where they differentiate into neurons that have dopamine markers. The presence of these new dopamine neurons is associated with dramatic improvement in sensorimotor and motor behavior.

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Fluorescence photomontage of a cross section of the left side of a rat’s brain.

The green-labeled cells at right are the new progenitor and adult stem cells that have divided along the ependymal and subventricular zones lining the ventricle adjacent to the striatum, which appears as a black area peppered with clusters of green progenitors migrating toward the stroke lesion at the lower left. The stroke lesion also contains newly formed progenitor cells stained red and green, which have migrated from the subventricular zone at right. Connecting this zone and the site of the healing stroke site is an area of migrating green progenitors. Thus, the adult stem cells migrate from upper right to lower left. TGFα was injected into the brain area overlapping the stroke site.

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Cross section of the brain (similar to Fig 01) illustrating how TGFα acts to repair damage in the brain of patients (and animal models) with chronic stroke.

At the right are the key brain structures involved, including the striatum, the pallidum, the thalamus, and the midbrain dopamine neurons of the substantia nigra-ventral tegmental area. At left the cortical-striatal pallidal-nigral-thalamic-cortical “loop” is shown. In chronic stroke, all the neurons in the central (umbra) stroke area die and must be replaced by new neurons and proper connections. TGFα infused into the stroke area of striatum, pallidum, and/or cortex, (or intranasally), induces the adult stem cells lining the ependymal and subventricular zone adjacent to the striatum to divide (proliferation) in great numbers (hundreds of thousands to millions of new progenitors) and then migrate to the regions of the striatum, pallidum, and cortex where they differentiate into neurons that have the appropriate brain area markers, whether they be striatal, pallidal, or cortical in nature. The replacement of these new neurons is associated with dramatic improvement in sensorimotor and motor behavior.

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Sagittal (side) view of the brain and head (inset at right) illustrating intracranially or intranasally infused TGFα into the brain containing a chronic stroke.

Using both application methods, the TGFα is able to diffuse and reach the ependymal and subependymal zones of the brain to stimulate “quiet” adult stem cells and induce them to divide into massive numbers of new progenitor cells which migrate to zones of damage in the brain, in this case, chronic stroke.

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Research Papers

Intranasal Administration of PEGylated Transforming Growth Factor-α Improves Behavioral Deficits in a Chronic Stroke Model

Transforming Growth Factor-Alpha Induces Neurogenisis And Behavioral Improvement In a Chronic Stroke Model