Table 1 Summarizing the data of all preclinical studies in PD specifying the design, objectives, methodology, results, and conclusion

19

rTMS intermittent theta-burst stimulation in 6-OHDA-hemilesioned rats

To evaluate the effect of rTMS on glial activation and dopaminergic function in PD rats

rTMS stimulation with intermittent theta-burst for PD model rats

- Significant downregulation of astrocytic and microglial responses

rTMS significantly modulates glial activation and improves dopaminergic function, demonstrating potential for PD treatment

- CX3 CL1 levels reduced

- Restoration of dopaminergic function in striatal neurons

20

DBS stimulation in the subthalamic nucleus (STN) in 6-OHDA-treated rats

To assess the effects of STN-DBS on microglial activation and cytokine expression in PD model rats

DBS stimulation of the STN in 6-OHDA-treated rats

- Decrease in CX3 CL1, CX3 CR1, and Iba-1 levels

STN-DBS suppresses glial activation and reduces pro-inflammatory cytokine levels, promoting neuroprotection

- Reduced microglial activation

- Decrease in IL-1β, IL-6, and TNF-α levels in the ventral midbrain

21

DBS stimulation in naive rats in the subthalamic nucleus (STN)

To study the impact of DBS on glial activation in non-diseased rats

DBS stimulation applied to naive rats in the subthalamic nucleus

- Decreased activation of microglia

DBS reduces microglial activation in naive rats, supporting its potential use in neuroprotection

- Less glial cell activation compared to microlesioned and sham rats

22

High-frequency stimulation (HFS) applied to cultured astrocytes in vitro

To investigate the effects of HFS-DBS on astrocyte activation and inflammatory response in vitro

High-frequency stimulation (HFS) applied to cultured astrocytes along with cytokine induction and NF-κB activation

- Attenuation of astrocyte activation

HFS-DBS regulates astrocyte activation and inflammatory response, suggesting potential for modulation of neuroinflammation

- Regulation of the inflammatory response through NF-κB modulation

23

ECT and mesenchymal stem cells (MSCs) in a mouse PD model

To explore the synergistic effect of ECT and MSCs on dopaminergic function and neuroprotection

ECT treatment combined with MSCs in a mouse model of PD

- Enhanced differentiation of MSCs into dopaminergic neurons

ECT and MSCs exhibit synergistic effects in PD treatment, enhancing dopaminergic neuron differentiation and neuroprotection

- Upregulation of MSC dopamine levels

- Improved neuroprotection and motor performance

24

aVNS treatment in 6-OHDA-treated rats

To assess the effect of aVNS on immune modulation and neuronal protection in PD

aVNS treatment administered 7 days after 6-OHDA lesioning in rats, stimulating the medial forebrain bundle

- Decrease in IL-1β and TNF-α levels

aVNS modulates the immune response and suppresses inflammation, leading to neuroprotective effects in PD

- Upregulation of Tregs and reduction of Th17 cells

- Protection of dopaminergic neurons in substantia nigra

25

High-frequency stimulation (HFS-DBS) in a 6-OHDA disease rat model

To evaluate the impact of HFS-DBS on cytokine expression and glial activation in PD

HFS-DBS applied to rats with a focus on the inflammatory response and cytokine expression

- Decrease in MCP-1 levels and TNF-α and NF-κB activation

HFS-DBS regulates cytokine expression and suppresses glial activation, suggesting a neuroprotective role in PD

- Downregulation of inflammasome reactivity

- Suppression of morphological changes in astrocytes

- Reduction in neuroinflammation

26

Electrode-human brain tissue interface study via SEM and TEM

To investigate the clinical implications of the electrode surface in DBS response

Scanning (SEM) or transmission (TEM) electron microscopy to examine the interface between the electrode and human brain tissue

- Foreign-body multinucleate giant cell-type reaction observed

Electrode material properties may influence clinical outcomes in DBS treatments, with immune responses playing a role in therapy efficacy

- Fusion of microglia, macrophage precursors, and circulating monocytes

-Lysosomes with phagocytosed material in cells