Heterotopic Mucosal Grafting Enables the Delivery of Therapeutic Neuropeptides Across the Blood Brain Barrier.
BACKGROUND
The blood-brain barrier represents a fundamental limitation in treating neurological disease because it prevents all neuropeptides from reaching the central nervous system (CNS). Currently, there is no efficient method to permanently bypass the blood-brain barrier.


OBJECTIVE
To test the feasibility of using nasal mucosal graft reconstruction of arachnoid defects to deliver glial-derived neurotrophic factor (GDNF) for the treatment of Parkinson disease in a mouse model.


METHODS
The Institutional Animal Care and Use Committee approved this study in an established murine 6-hydroxydopamine Parkinson disease model. A parietal craniotomy and arachnoid defect was repaired with a heterotopic donor mucosal graft. The therapeutic efficacy of GDNF (2 μg/mL) delivered through the mucosal graft was compared with direct intrastriatal GDNF injection (2 μg/mL) and saline control through the use of 2 behavioral assays (rotarod and apomorphine rotation). An immunohistological analysis was further used to compare the relative preservation of substantia nigra cell bodies between treatment groups.


RESULTS
Transmucosal GDNF was equivalent to direct intrastriatal injection at preserving motor function at week 7 in both the rotarod and apomorphine rotation behavioral assays. Similarly, both transmucosal and intrastriatal GDNF demonstrated an equivalent ratio of preserved substantia nigra cell bodies (0.79 ± 0.14 and 0.78 ± 0.09, respectively, P = NS) compared with the contralateral control side, and both were significantly greater than saline control (0.53 ± 0.21; P = .01 and P = .03, respectively).


CONCLUSIONS
Transmucosal delivery of GDNF is equivalent to direct intrastriatal injection at ameliorating the behavioral and immunohistological features of Parkinson disease in a murine model. Mucosal grafting of arachnoid defects is a technique commonly used for endoscopic skull base reconstruction and may represent a novel method to permanently bypass the blood-brain barrier.
‡Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts; §Department of Biomedical Engineering, Boston University, Boston, Massachusetts; ¶Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Benjamin S
BS
Bleier
Richie E
RE
Kohman
Kevin
K
Guerra
Angela L
AL
Nocera
Shreshtha
S
Ramanlal
Armine H
AH
Kocharyan
William T
WT
Curry
Xue
X
Han
D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D003399:Craniotomy / Q000379:methods; D004195:Disease Models, Animal; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage*; D051379:Mice; D009092:Mucous Membrane / Q000637:transplantation*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000166:cytology
D051100:Glial Cell Line-Derived Neurotrophic Factor; D018696:Neuroprotective Agents