Abstract
Deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) is effective in treating temporal lobe epilepsy (TLE) and protects hippocampal neurons. Autophagy plays an essential role in epileptogenesis; however, the underlying effect of autophagy on ANT-DBS-mediated neuroprotection remains unclear. A monkey model of epilepsy was established by injecting kainic acid into the hippocampus and amygdala using a robot-assisted system. ANT-DBS was delivered in the chronic stage of the epileptic model and continued for 8 weeks. We found that ANT-DBS reduced the frequency of seizures and exerted neuroprotective effects via activating autophagy in hippocampal neurons. ANT-DBS increased light chain 3 (LC3) II level and co-localization of LC3 and lysosomal-associated membrane protein-1, accompanied by decreased expression of the autophagy substrate ubiquitin-binding protein p62, suggesting increased autophagosome formation. Most importantly, brain-derived neurotrophic factor (BDNF) –tropomyosin-related kinase type B (TrkB) pathway were involved in the regulation of autophagy. Both protein levels were reduced by ANT-DBS, and there was less phosphorylation of downstream regulators, extracellular signal-regulated kinase and Akt, followed by inactivation of mammalian target of rapamycin complex 1. Taken together, chronic ANT-DBS exerts neuroprotective effects on hippocampal neurons through inducing autophagy via suppressing the BDNF–TrkB pathway in a TLE monkey model.
Highlights
Epilepsy is characterized by a predisposition to generating recurrent seizures with neurobiological, cognitive, psychological and social consequences [1]
We successfully established the nonhuman primates (NHP)-temporal lobe epilepsy (TLE) model, which was verified by behavior and SEEG monitoring, and studied the role of autophagy in the neuroprotective effects of Anterior nucleus of the thalamus (ANT)-deep brain stimulation (DBS) against KAinduced neuronal injury
The results showed that ANT-DBS-mediated hippocampal neurons protection in epileptic animals associated with increased autophagic activity which in turn was related to brain-derived neurotrophic factor (BDNF)-tropomyosin-related kinase type B (TrkB) signaling pathways and kainic acid (KA)-induced apoptosis (Figure 8)
Summary
Epilepsy is characterized by a predisposition to generating recurrent seizures with neurobiological, cognitive, psychological and social consequences [1]. Anterior nucleus of the thalamus (ANT) is the most frequently used deep brain stimulation (DBS) targets for drug-resistant temporal lobe epilepsy (TLE) [3]. It has already been found that ANT-DBS www.aging-us.com has a protective effect on the hippocampal neurons [9, 10], but the underlying mechanism still needs to be elucidated. Inhibition of the mammalian target of rapamycin complex (mTORC) function by rapamycin or a ketogenic diet can promote autophagy and control epilepsy [16]. One of the most important upstream inhibitors of autophagy is brain-derived neurotrophic factor (BDNF), which acts via activation of its highaffinity receptor tropomyosin-related kinase type B (TrkB). The seizure-induced expression of neurotrophic factors might contribute to the lasting structural and functional changes underlying epileptogenesis, like mossy fiber sprouting [19,20,21]. The effect of autophagy on ANT-DBS-mediated neuroprotection has not been elucidated
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