Abstract
Focused ultrasound-enhanced intranasal (IN + FUS) delivery is a noninvasive approach that utilizes the olfactory pathway to administer pharmacological agents directly to the brain, allowing for a more homogenous distribution in targeted locations compared to IN delivery alone. However, whether such a strategy has therapeutic values, especially in neurodegenerative disorders such as Parkinson’s disease (PD), remains to be established. Herein, we evaluated whether the expression of tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine catalysis, could be enhanced by IN + FUS delivery of brain-derived neurotrophic factor (BDNF) in a toxin-based PD mouse model. Mice were put on the subacute dosing regimen of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), producing bilateral degeneration of the nigrostriatal pathway consistent with early-stage PD. MPTP mice then received BDNF intranasally followed by multiple unilateral FUS-induced blood-brain barrier (BBB) openings in the left basal ganglia for three consecutive weeks. Subsequently, mice were survived for two months and were evaluated morphologically and behaviorally to determine the integrity of their nigrostriatal dopaminergic pathways. Mice receiving IN + FUS had significantly increased TH immunoreactivity in the treated hemisphere compared to the untreated hemisphere while mice receiving only FUS-induced BBB opening or no treatment at all did not show any differences. Additionally, behavioral changes were only observed in the IN + FUS treated mice, indicating improved motor control function in the treated hemisphere. These findings demonstrate the robustness of the method and potential of IN + FUS for the delivery of bioactive factors for treatment of neurodegenerative disorder.
Highlights
Advances in treatment of neurodegenerative disease have been greatly hindered due to the crucial, but obstructive, blood-brain barrier (BBB), which prevents majority of therapeutic drugs from entering the brain parenchyma through systemic circulation[1]
Mice with strong MR contrast enhancement in the accurately targeted region saw approximately an increase of 35% in the striatum and a 38% in the substantia nigra (SN) increase in the amount of brain-derived neurotrophic factor (BDNF) delivered when comparing the ipsilateral side to the contralateral side (n = 3)
In the striatum, where the degeneration begins, we found a ~20% increase in the expression of tyrosine hydroxylase (TH) in IN + FUS-mediated BBB opening only (FUS) BDNF treated mice, a significant improvement compared to mice receiving MPTP only and MPTP mice receiving FUS induced BBB opening alone
Summary
Advances in treatment of neurodegenerative disease have been greatly hindered due to the crucial, but obstructive, blood-brain barrier (BBB), which prevents majority of therapeutic drugs from entering the brain parenchyma through systemic circulation[1]. Current methods of drug delivery to the brain, such as direct injection, convection-enhanced delivery and osmotic BBB disruption, are targeted but highly invasive, making them non-ideal for chronic administration[2]. Noninvasive techniques such as molecular modification of drugs and formulation of brain-penetrating nanoparticles offer a safer alternative, but do not provide a targeted effect within the brain[3,4]. We hypothesize that any local changes in the treated nigrostriatal pathway would cause a biochemical and/or functional imbalance between hemispheres, which we elucidated through immunohistochemistry and behavioral testing
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