Focused ultrasound enhanced intranasal delivery of brain derived neurotrophic factor produces neurorestorative effects in a Parkinson’s disease mouse model

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.

Putting Cells in Motion: Advantages of Endogenous Boosting of BDNF Production

“…Even focused ultrasound has been proposed, and although invasive and not always effective [ 124 ], encouraging studies performed in a mouse model of PD have provided perspectives in the use of focused ultrasound for improving the delivery of intranasally administered BDNF within the brain [ 125 , 126 ]. In addition, therapeutic effects of the BDNF injection have been assessed in non-human primate models.…”

Intranasal Delivery: Effects on the Neuroimmune Axes and Treatment of Neuroinflammation

“…The authors declare no conflict of interest. Alter inflammatory pathways Improved memory [39,42] ↓ astrocyte/microglia activation [40,41] Improves neuroinflammation Improved memory [46] Traumatic brain injury ↓ lesion volume; ↓ microglia activation [47] FGF Alzheimer's disease ↑ neurogenesis; ↓ hippocampal loss Improved memory [49,50] ↓ Aβ deposition, tau hyperphosphorylation, astrocyte/microglia activation Improved memory [59] Neuroinflammation modifies microglia signaling, DAMPs, PAMPs [51] Parkinson's disease ↑ dopaminergic neuron function; ↓ astrocyte/microglia activation Improves behavioral deficit [53] Stroke (hypoxia/ischemia) ↓ pro-inflammatory cytokines [59] BDNF Depression Improved behavior [63] Parkinson's disease ↑ dopaminergic neurons Improved motor function [68] Stroke No change in infarct volume; altered neuroinflammatory profile [79] NGF Human GBS meningitis* Improved neurological impairment [83] Human traumatic brain injury* ↑ neurogenesis Improved neurological impairment [86] Traumatic brain injury ↓ edema and cell death [82] PACAP Alzheimer's disease ↓ RAGE Improved memory [26,88] Huntington's disease ↑ BDNF, synapses;↓ mutant huntingtin aggregates Improved memory [90] Muscular dystrophy (SBMA) ↑ polyQ-AR degradation; improve neurotoxicity [89] MSC-oligodendrocytes Multiple sclerosis (EAE) ↓ neuroinflammation; ↑ myelination Improved behavior [186] IGF-1, insulin-like growth factor-1; FGF, fibroblast growth factor; BDNF, brain-derived neurotrophic factor; NGF, nerve growth factor; PACAP, pituitary adenylate-cyclase-activating polypeptide 38; GBS, group B Streptococcus; SBMA, spinobulbar muscular atrophy; EAE, experimental autoimmune encephalomyelitis; NBP, DL-3-n-butylphthalide; TGF, transforming growth factor; G-CSF, granulocyte-colony stimulating factor; IL, interleukin; TNF, tumor necrosis factor; MSC, mesenchymal stem cell; EV, extracellular vesicle; PMN, polymorphonuclear neutrophils; DAMP, damage-associated molecular pattern; PAMP, pathogen-associated molecular pattern; RAGE, receptor for advanced glycation end products; polyQ-AR, polyglutamine androgen receptor; BBB, blood-brain barrier; Aβ, amyloid beta; P-gp, p-glycoprotein; VEGF, vascular endothelial growth factor; eNOS, endothelial nitric oxide synthase; Ido-1, indoleamine 2,3-dioxygenase; mTORC1, mammalian target of rapamycin complex 1.The effects following intranasal...…”

“…In 2014, Chen and colleagues advanced the CNS delivery of BDNF, while reducing peripheral confounds, by combining IN delivery of BDNF with focused ultrasound (FUS). This technique was then applied to improve the outcome in a rat model for human PD [ 68 ].…”

Focused Ultrasound-Enhanced Delivery of Intranasally Administered Anti-Programmed Cell Death-Ligand 1 Antibody to an Intracranial Murine Glioma Model

“…Focused ultrasound (FUS)-mediated intranasal delivery (FUSIN) harvests the unique advantages of intranasal (IN) administration for direct nose-to-brain drug administration with minimized systemic exposure and of FUS in combination with microbubbles for targeted and enhanced delivery to the brain [ 9 , 10 , 11 , 12 ]. FUS-induced microbubble cavitation pushes and pulls on the adjacent blood vessel [ 13 ], generating the hypothesized “microbubble pumping effect”.…”

“…The microbubble pumping effect is hypothesized to enhance the penetration and accumulation of IN-administered drugs. FUSIN has been utilized to deliver multiple agents, including dextrans, gold nanoparticles, and protein drugs to the FUS-targeted region with high efficiency and minimized systemic exposure [ 10 , 12 , 14 , 15 ]. The previous work suggests that FUSIN is a promising brain drug delivery technique that can enhance the delivery efficiency of different agents to different brain regions; however, no study has been performed to evaluate the potential of FUSIN in the delivery of ICIs to the glioma.…”