The role of neuromodulation in the management of drug-resistant epilepsy

Salama, HusamEddin; Salama, Ahmed; Oscher, Logan; Jallo, George I.; Shimony, Nir

doi:10.1007/s10072-024-07513-9

Cited by 4 publications

(1 citation statement)

References 112 publications

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“…While RIPK3 signaling appears to represent an endogenous mechanism of neuroprotection during flavivirus-induced neurotoxicity, this phenomenon supports the idea that pharmacologic interventions that suppress glutamatergic neurotransmission and/or engage CREB-dependent neuroprotection may have therapeutic potential during neuroinvasive flavivirus infection, particularly during acute encephalitis 23 . The role of hyperexcitation in neuronal cell death during these infections also raises the possibility that non-pharmacologic strategies such as neuromodulation 78,79 may have some benefit, though testing this hypothesis will require extensive mechanistic study. In any case, identifying new strategies to preserve CNS health during flavivirus infections is of critical importance given the significant and growing burden flaviviruses pose to global public health.…”

Section: Discussionmentioning

confidence: 99%

RIPK3 promotes neuronal survival by suppressing excitatory neurotransmission during CNS viral infection

Estevez,

Buckley,

Panzera

et al. 2024

Preprint

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While recent work has identified roles for immune mediators in the regulation of neural activity, the capacity for cell intrinsic innate immune signaling within neurons to influence neurotransmission remains poorly understood. However, the existing evidence linking immune signaling with neuronal function suggests that modulation of neurotransmission may serve previously undefined roles in host protection during infection of the central nervous system. Here, we identify a specialized function for RIPK3, a kinase traditionally associated with necroptotic cell death, in preserving neuronal survival during neurotropic flavivirus infection through the suppression of excitatory neurotransmission. We show that RIPK3 coordinates transcriptomic changes in neurons that suppress neuronal glutamate signaling, thereby desensitizing neurons to excitotoxic cell death. These effects occur independently of the traditional functions of RIPK3 in promoting necroptosis and inflammatory transcription. Instead, RIPK3 promotes phosphorylation of the key neuronal regulatory kinase CaMKII, which in turn activates the transcription factor CREB to drive a neuroprotective transcriptional program and suppress deleterious glutamatergic signaling. These findings identify an unexpected function for a canonical cell death protein in promoting neuronal survival during viral infection through the modulation of neuronal activity, highlighting new mechanisms of neuroimmune crosstalk.

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Section: Discussionmentioning

confidence: 99%