New Blood–Brain Barrier Models Using Primary Parkinson’s Disease Rat Brain Endothelial Cells and Astrocytes for the Development of Central Nervous System Drug Delivery Systems

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor system defects due to the loss of dopaminergic neurons. A significant contributor to the current limited therapeutic treatments for PD is the poor penetration of potential drugs through the blood−brain barrier (BBB). The BBB is a highly specialized neurovascular system that separates components of the circulating blood from neurons. There is a great need to develop in vitro BBB models that retain fundamental characteristics and reliably predict the permeability of drug candidates. BBB breakdown may initiate and/or contribute to neuronal dysfunction and loss in diseases such as PD. However, there is no in vitro BBB model that mimics the pathological state of PD. To construct in vitro BBB models for drug delivery systems in the developing central nervous system (CNS), we isolated high purity endothelial cells from both normal and PD rat brain microvessels. The primary rat endothelial cell cultures maintained the properties of their in vivo counterparts. We developed and characterized in vitro rat endothelial cell and C6 glial cell coculture BBB models. We further examined the morphological and functional integrity of the barriers. The in vitro coculture BBB models we established displayed the typical cytoarchitecture and cellular markers by immunofluorescence staining and electron microscopy, high transendothelial electrical resistance (>300 Ω cm 2 ), and a low permeability value (<3 × 10 −6 cm/s). Our new models can be used to study BBB dysfunctions in relation to the pathogenesis and progression of PD, as well as a screening tool to test candidate drugs for PD treatment.

Parkinson's Disease: Current Status, Diagnosis, and Treatment Using Nanomedicines

“…The clinical manifestations of PD and pathophysiological signs vary depending on the type of gene mutation. [8,28,29] In addition, the impairment of 𝛼-syn function and the accumulation are both directly correlated with some gene alterations. Disruption of 𝛼-syn function and accumulation is a direct result of PARK 1, PARK 4, and LRRK2 gene alterations.…”

“…Other pathways, such as receptor‐mediated transcytosis (RMT), carrier‐mediated transcytosis (CMT), cell‐mediated transport, and adsorptive‐mediated transcytosis (AMT), are important transport routes for the transportation of foreign substances into the brain. [ 7,8 ] Brain‐targeted nanoparticle (NP) delivery strategies can achieve effective BBB penetration by utilizing endogenous BBB transport routes. By taking advantage of recent advances in BBB technology, including ultrasound technology, peptide‐based technology, and microfluidic technology, many NPs, including organic NPs, exosomes, liposomes, and inorganic NPs, show promise for effective systemic brain drug delivery.…”

Exposure of quantum dots in the nervous system: Central nervous system risks and the blood–brain barrier interface

“…The BBB significantly hinders drug delivery to the CNS, especially for the treatment of Alzheimer's disease (AD) (Cai et al, 2021; Palma‐Florez et al, 2023). To improve the efficiency with which medicines get delivered without compromising the integrity of the BBB, drug delivery via nanoparticles (NPs) has emerged as a favored therapeutic approach (Zhang et al, 2022).…”

Modeling the blood-brain barrier for treatment of central nervous system (CNS) diseases

“…Using a Transwell model, Cai et al 108 primarily focused on the comparison of normal rat endothelial cells to the PD rat endothelial cells and the drug delivery potential of each model in the treatment of PD. In order to create the PD rat model, it was injected with 6-OHDA, a neuron toxin that attacks the same areas of the brain as PD.…”