Unraveling the Role of Astrocytes in Subthalamic Nucleus Deep Brain Stimulation in a Parkinson’s Disease Rat Model

Abstract

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective therapeutic strategy for motor symptoms of Parkinson's disease (PD) when L-DOPA therapy induces disabling side effects. Classical inflammatory activation of glial cells is well established in PD, contributing to the progressive neurodegenerative state; however, the role of DBS in regulating the inflammatory response remains largely unknown. To understand the involvement of astrocytes in the mechanisms of action of DBS, we evaluated the effect of STN-DBS in regulating motor symptoms, astrocyte reactivity, and cytokine expression in a 6-OHDA-induced PD rat model. To mimic in vivo DBS, we investigate the effect of high-frequency stimulation (HFS) in cultured astrocytes regulating cytokine induction and NF-κB activation. We found that STN-DBS improved motor impairment, induced astrocytic hyperplasia, and reversed increased IFN-γ and IL-10 levels in the globus pallidus (GP) of lesioned rats. Moreover, HFS activated astrocytes and prevented TNF-α-induced increase of monocyte chemoattractant protein-1 (MCP-1) and NF-κB activation in vitro. Our results indicate that DBS/HFS may act as a regulator of the inflammatory response in PD states, attenuating classical activation of astrocytes and cytokine induction, potentially through its ability to regulate NF-κB activation. These findings may help us understand the role of astrocyte signaling in HFS, highlighting its possible relationship with the effectiveness of DBS in neurodegenerative disorders.

Subthalamic Deep Brain Stimulation Affects Plasma Corticosterone Concentration and Peripheral Immunity Changes in Rat Model of Parkinson’s Disease

“…After DBS electrode implantation, regional neuroinflammation in the rats was observed with concomitant memory impairment (Hirshler et al 2010 ); in the macaque, reactive gliosis was seen after 3 months and 3 years (Griffith and Humphrey 2006 ); and in the human, reactive gliosis was observed in a postmortem study 12 years after implantation in an essential tremor patient with good tremor control (DiLorenzo et al 2010 ). Recent study by Campos et al ( 2020 ) showed that DBS activated astrocytes and prevented TNF-α-induced increase of monocyte chemoattractant protein-1 (MCP-1) and NF-κB activation in vitro. In the same study, 6-OHDA microinjection into the SN induced an increase in the number of GFAP-positive cells in the globus pallidus (GP) 13 days after PD model induction, but also influenced IFN-γ induction.…”

“…In the same study, 6-OHDA microinjection into the SN induced an increase in the number of GFAP-positive cells in the globus pallidus (GP) 13 days after PD model induction, but also influenced IFN-γ induction. In addition, 6-OHDA-induced IFN-γ was completely attenuated by DBS-STN (Campos et al 2020 ). The above data suggests that in both stimulated groups, the peripheral immunity changes after DBS-STN could depend on the combined neuronal–glial interactions and influence on hormone balance.…”

Motor Cortex Stimulation Reversed Hypernociception, Increased Serotonin in Raphe Neurons, and Caused Inhibition of Spinal Astrocytes in a Parkinson’s Disease Rat Model

“…The PD induction model was made as previously described [ 25 , 54 ]. Animals were anesthetized with isoflurane (4% induction, 2.5% maintenance in 100% oxygen) associated with local anesthesia (2% lidocaine, 100 μL/animal on the scalp).…”

Neuroimaging evaluation of deep brain stimulation in the treatment of representative neurodegenerative and neuropsychiatric disorders

“…This has been used successfully to detect neuroinflammation in cortical and subcortical regions in intervention studies and neurological disorders such as PD, AD and epilepsy (Gershen et al, 2015 , Jucaite et al, 2015 , Sandiego et al, 2015 , Kreisl et al, 2017 ). Modulation of neuroinflammatory response by DBS has been suggested as a potential therapeutic strategy in animal models of neurodegenerative diseases (Campos et al, 2020 , Chen et al, 2020 ) although this has not been demonstrated in patient populations. Nevertheless, VNS has been shown to impact immunity in the brain and many other organ systems upstream and downstream the site of stimulation (Pavlov, 2019 ).…”