Electrical Stimulation of the Mesencephalic Locomotor Region Attenuates Neuronal Loss and Cytokine Expression in the Perifocal Region of Photothrombotic Stroke in Rats

Abstract

Deep brain stimulation of the mesencephalic locomotor region (MLR) improves the motor symptoms in Parkinson’s disease and experimental stroke by intervening in the motor cerebral network. Whether high-frequency stimulation (HFS) of the MLR is involved in non-motor processes, such as neuroprotection and inflammation in the area surrounding the photothrombotic lesion, has not been elucidated. This study evaluates whether MLR-HFS exerts an anti-apoptotic and anti-inflammatory effect on the border zone of cerebral photothrombotic stroke. Rats underwent photothrombotic stroke of the right sensorimotor cortex and the implantation of a microelectrode into the ipsilesional MLR. After intervention, either HFS or sham stimulation of the MLR was applied for 24 h. The infarct volumes were calculated from consecutive brain sections. Neuronal apoptosis was analyzed by TUNEL staining. Flow cytometry and immunohistochemistry determined the perilesional inflammatory response. Neuronal apoptosis was significantly reduced in the ischemic penumbra after MLR-HFS, whereas the infarct volumes did not differ between the groups. MLR-HFS significantly reduced the release of cytokines and chemokines within the ischemic penumbra. MLR-HFS is neuroprotective and it reduces pro-inflammatory mediators in the area that surrounds the photothrombotic stroke without changing the number of immune cells, which indicates that MLR-HFS enables the function of inflammatory cells to be altered on a molecular level.

Electrical Stimulation of the Mesencephalic Locomotor Region Has No Impact on Blood–Brain Barrier Alterations after Cerebral Photothrombosis in Rats

“…In particular, the importance of inflammatory pathways regarding injury of BBB has been suggested by several studies, whereas chemokines and cytokines are key players in this context [12,13]. Recently, we have shown that MLR-HFS ipsilateral to the lesion enables restoring gait impairment in rats with photochemically induced stroke in the sensorimotor cortex [9], but also attenuates inflammatory processes in the perilesional area when HFS is applied during 24 h in the early course after induction of photothrombotic stroke [10]. Therefore, we hypothesized that this anti-inflammatory effect of MLR-HFS might contribute—at least in part—to the stabilization of the BBB after ischemic stroke.…”

“…These findings might be explained by an attenuated cerebral inflammation or change of the cerebral microvasculature due to electrical modulation of the parasympathetic innervation. Recently, we have shown that DBS of the mesencephalic locomotor region (MLR) improves gait function [9], but also reduces inflammatory processes in the perilesional area of a photothrombotic stroke model [10]. The MLR is a functionally defined region of the brainstem encompassing the cuneiform, pedunculopontine tegmental, and mesencephalic reticular nucleus [11], which is connected indirectly with the cerebral cortex.…”

Electrical stimulation inhibits Val-boroPro-induced pyroptosis in THP-1 macrophages via sirtuin3 activation to promote autophagy and inhibit ROS generation

“…Different cells respond differently to electrical stimulation (ES), which may alter electrophysiological activity in electrogenic cells, or induce proliferation or differentiation in non-electrogenic cells [29]. ES significantly reduced the release of cytokines and chemokines within the ischemic penumbra [30]. Another study found that low-frequency ES attenuated muscle atrophy in a mouse model of chronic kidney disease by stimulating myogenesis and inducing delayed M2 polarization of infiltrating macrophages [31].…”

Mesencephalic Electrical Stimulation Reduces Neuroinflammation after Photothrombotic Stroke in Rats by Targeting the Cholinergic Anti-Inflammatory Pathway

“…After focal cerebral ischemia, proinflammatory cytokines such as interleukin (IL)-1 or tumor necrosis factor (TNF)-α are strongly induced [ 1 , 2 ]. We and others have shown that invasive electrical stimulation of distinct brain areas such as the fastigial nucleus, cerebral cortex, or mesencephalic locomotor region (MLR) may attenuate neuroinflammation [ 3 , 4 , 5 ]. In particular, high-frequency stimulation (HFS) within or close to the cuneiform nucleus (Cn) resulted in a significant reduction of proinflammatory cytokines and chemokines in the perilesional area of a photothrombotic stroke (PTS) ipsilesional to the stimulated site [ 4 ].…”

“…We and others have shown that invasive electrical stimulation of distinct brain areas such as the fastigial nucleus, cerebral cortex, or mesencephalic locomotor region (MLR) may attenuate neuroinflammation [ 3 , 4 , 5 ]. In particular, high-frequency stimulation (HFS) within or close to the cuneiform nucleus (Cn) resulted in a significant reduction of proinflammatory cytokines and chemokines in the perilesional area of a photothrombotic stroke (PTS) ipsilesional to the stimulated site [ 4 ]. However, the effect of electrical stimulation on putative neural regulation of inflammatory processes is not well understood.…”