Abstract
The relationship between extracellular space (ECS) diffusion parameters and brain drug clearance is not well-studied, especially in the context of Parkinson's disease (PD). Therefore, we used a rodent model of PD to explore the distribution and clearance of a magnetic resonance tracer. Forty male Sprague Dawley rats were randomized into four different groups: a PD group, a Madopar group (PD + Madopar treatment), a sham group, and a control group. All rats received an injection of the extracellular tracer gadolinium-diethylene triaminepentacetic acid (Gd-DTPA) directly into the substantia nigra (SN). ECS diffusion parameters including the effective diffusion coefficient (D*), clearance coefficient (k'), ratio of the maximum distribution volume of the tracer (Vd-max%), and half-life (t1/2) were measured. We found that all parameters were significantly increased in the PD group compared to the other three groups (D*: F = 5.774, p = 0.0025; k': F = 20.00, P < 0.0001; Vd-max%: F = 12.81, P < 0.0001; and t1/2: F = 23.35, P < 0.0001). In conclusion, the PD group exhibited a wider distribution and lower clearance of the tracer compared to the other groups. Moreover, k' was more sensitive than D* for monitoring morphological and functional changes in the ECS in a rodent model of PD.
Highlights
Parkinson’s disease (PD) is a common neurodegenerative disorder that is characterized by progressive motor and cognitive impairments
We found that diffusion coefficient (D∗)was higher in the PD group than that of the other three groups ([2.744 ± 0.341] × 10−4 mm2/s in the PD group vs. [2.340 ± 0.448] ×10−4 mm2/s in the Madopar drug group, [2.078 ± 0.326] ×10−4 mm2/s in the sham group, and [2.023 ± 0.501] × 10−4 mm2/s in the control group; F = 5.774, P = 0.0025, Figure 1A); differences among the Madopar, sham, and control groups were non-significant (P = 0.185 and P = 0.111, respectively; least significant difference (LSD))
Distribution volume-time profiles are shown in Figure 1D and demonstrate that the Vdmax% of gadolinium-diethylene triaminepentacetic acid (Gd-DTPA) was higher in the PD group (2.392 ± 0.185%) than that of the Madopar group (2.153 ± 0.102%), sham group (2.091 ± 0.110%), and control group (2.054 ± 0.090%; F = 12.81, P < 0.0001, Figure 1B)
Summary
Parkinson’s disease (PD) is a common neurodegenerative disorder that is characterized by progressive motor and cognitive impairments. Researchers focused on the genetic underpinnings of Parkinson’s disease (Ma et al, 2013), and searched for some new methods that may affect the neurodegeneration processes in it (Chen et al, 2016). Such as this, stem cell therapy of PD had shown great potential in retarding the loss of dopaminergic neurons and minimizing the behavioral abnormalities (Salama et al, 2017). Some research has focused on direct drug delivery to the brain ECS as a method to bypass the BBB (Barua et al, 2014, 2015)
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