Amelioration of the nigrostriatal pathway facilitated by ultrasound-mediated neurotrophic delivery in early Parkinson's disease

Abstract

The blood-brain barrier (BBB) prevents most drugs from gaining access to the brain parenchyma, which is a recognized impediment to the treatment of neurodegenerative disorders like Parkinson's disease (PD). Focused ultrasound (FUS), in conjunction with systemically administered microbubbles, opens the BBB locally, reversibly and non-invasively. Herein, we show that neither FUS applied over both the striatum and the ventral midbrain, without neurotrophic factors, nor intravenous administration of neurotrophic factors (either through protein or gene delivery) without FUS, ameliorates the damage to the nigrostriatal dopaminergic pathway in the sub-acute MPTP mouse model of early-stage PD. Conversely, the combination of FUS and intravenous

Blood–brain barrier opening with focused ultrasound in experimental models of Parkinson's disease

“…This intervention has shown efficacy in delivering various compounds of different molecular weights into the brain parenchyma, including contrast agents, sugars, antibodies, chemotherapeutics, and neurotrophic factors . Aside from the direct delivery of the pharmacological agent, FUS‐facilitated viral and nonviral vector‐based gene delivery has been proven feasible to promote the long‐term expression of endogenous proteins …”

“…Figure adjusted from Samiotaki and colleagues . Horizontal section at the striatum, outlined by the red dotted lines, immunostained against neurturin (NTN; brown color), and counterstained with hematoxylin (purple color).…”

“…Following the initial feasibility study, Karakatsani and colleagues delivered adeno‐associated virus (AAV)–GDNF (AAV1‐CAG‐eGFP‐GDNF) in the left striatum and midbrain of subacute MPTP‐treated mice. Dopaminergic neuronal cell bodies demonstrated a 58.4% upregulation with more than a twofold increase in their projections’ density after the administration of AAV‐GDNF and its diffusion through the FUS‐induced BBB opening, as evidenced by tyrosine hydroxylase (TH) immunostaining.…”

“…Figure adjusted from Karakatsani and colleagues . The nigrostriatal pathway includes the substantia nigra (SN), where the dopaminergic neuronal cells (SNc) and dendrites (SNr) lie, and the striatum, where the neuronal terminals can be found.…”

“…To determine the potential value of using FUS to improve the brain penetrance of bioactive molecules of the compromised neurons in the neurodegenerated brain, Karakatsani and colleagues compared TH‐based parameters between hemispheres of the MPTP‐injected mice that received single or triple systemic NTN injections coupled with the equivalent number of FUS applications (Fig. ).…”