Radiation and regeneration: behavioral improvement and GDNF expression after Gamma Knife radiosurgery in the 6-OHDA rodent model of hemi-parkinsonism.
BACKGROUND
Recent research has demonstrated that the adult mammalian CNS is capable of regeneration. This regeneration is often initiated as a response to thermal, chemical or mechanical injury. The effects of radiation on the mammalian CNS have also been found to aid in certain regeneration processes.


METHODS
In our project we examined the potential therapeutic value of radiation induced regeneration of diseased mammalian rat CNS. Eleven Sprague-Dawley rats with 6-hydroxy-dopamine (6-OHDA) induced hemi-parkinsonism were treated in the Leksell Gamma Knife using a single 4 mm collimator shot targeted to the ipsilateral (parkinsonian) caudate-putamen complex. A maximum dose of 140 Gy was used to create a necrotic lesion. Animals were tested behaviorally using the apomorphine-induced rotational behavior model before and up to 6 months after radiosurgery. Histochemical analysis was performed 2 weeks, 1 month and 4 months after radiosurgery. Histological sections were obtained and immunohistochemistry was performed for glial cell line derived neurotrophic factor (GDNF).


RESULTS
The rotational behavior for 11/11 animals (100%) was found to initially worsen at 2 weeks and 4 weeks after radiosurgery before a statistically highly significant reduction in apomorphine induced rotations was observed at 2, 3, and 4 months after radiosurgery (83% reduction by month four; p < 0.0001). For 2/11 animals the rotational behavior almost disappeared indicating near-abolition of parkinsonian behavior. On histological examination, the lesions were easily identified as areas of necrosis about 4 mm in diameter. The region immediately adjacent to the lesion was found to have highly positive expression of GDNF indicating high activity in dopamine-regenerating processes.


CONCLUSIONS
In this preliminary study we demonstrated that radiosurgical lesioning with the Gamma Knife into the striatum of hemi-parkinsonian animals resulted in significant behavioral improvement of signs of parkinsonism. Since GDNF expression is tightly linked to the dopaminergic system, we conclude that focused radiation is potentially capable of inducing regeneration of dopaminergic pathways in the adult CNS. Further studies with dose deescalation and molecular biological characterization of the regeneration cascades are necessary to gain access to potential clinical value of our observations.
Zerris
V A
VA
Department of Clinical Neurosciences (Neurosurgery), New England Gamma Knife Center, Brown University, Providence, Rhode Island, USA.
Zheng
Z
Z
Noren
G
G
Sungarian
A
A
Friehs
G M
GM
D000818:Animals; D002421:Caudate Nucleus / Q000473:pathology / Q000601:surgery; D004292:Dominance, Cerebral / Q000502:physiology; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007124:Immunoenzyme Techniques; D008297:Male; D009043:Motor Activity / Q000502:physiology; D009336:Necrosis; D009414:Nerve Growth Factors / Q000378:metabolism*; D009416:Nerve Regeneration / Q000502:physiology*; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000473:pathology / Q000601:surgery*; D011699:Putamen / Q000473:pathology / Q000601:surgery; D016634:Radiosurgery; D051381:Rats; D017207:Rats, Sprague-Dawley; D013239:Stereotyped Behavior / Q000502:physiology
C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D016627:Oxidopamine