Abstract
Sirtuin 1 (SIRT1) activity is neuroprotective, and we have recently demonstrated its role in the retrograde degenerative process in motoneurons (MNs) in the spinal cord of rats after peripheral nerve root avulsion (RA) injury. SIRT2 has been suggested to exert effects opposite those of SIRT1; however, its roles in neurodegeneration and neuron response after nerve injury remain unclear. Here we compared the neuroprotective potentials of SIRT1 activation and SIRT2 inhibition in a mouse model of hypoglossal nerve axotomy. This injury induced a reduction of around half MN population within the hypoglossal nucleus by a non-apoptotic neurodegenerative process triggered by endoplasmic reticulum (ER) stress that resulted in activation of the unfolded protein response mediated by IRE1α and XBP1 by 21 days post injury. Both SIRT1 activation with NeuroHeal and SIRT2 inhibition with AK7 protected NSC-34 motor neuron-like cells against ER stress in vitro. In agreement with the in vitro results, NeuroHeal treatment or SIRT1 overexpression was neuroprotective of axotomized hypoglossal MNs in a transgenic mouse model. In contrast, AK7 treatment or SIRT2 genetic depletion in mice inhibited damaged MN survival. To resolve the in vitro/in vivo discrepancies, we used an organotypic spinal cord culture system that preserves glial cells. In this system, AK7 treatment of ER-stressed organotypic cultures was detrimental for MNs and increased microglial nuclear factor-κB and the consequent transcription of cytotoxic pro-inflammatory factors similarly. The results highlight the importance of glial cells in determining the neuroprotective impact of any treatment.
Highlights
Axonopathy is a common early characteristic of the neurodegenerative processes in the central nervous system[1]
Apoptotic hallmarks, such as activation of caspase-3 or apoptosis-inducing factor (AIF) nuclearization, were not observed, MNs were degenerating as revealed by Fluoro-Jade C staining at 7 dpi (Fig. 1b)
To explore whether there was activation of endoplasmic reticulum (ER) stress in the hypoglossal axotomy model, we analyzed the expression of target genes of the unfolded protein response (UPR) activated after ER stress, as Chop, Grp[78], Xbp[1], and its spliced version (Xbp1s), as well as the activation of three main branches of UPR, PKR-like ER kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6), by western blot
Summary
Axonopathy is a common early characteristic of the neurodegenerative processes in the central nervous system[1]. Romeo-Guitart et al Cell Death and Disease (2018)9:531 retrograde neurodegenerative process that does not end in apoptosis[2, 3]. This knowledge has been useful in the discovery of effective neuroprotectants such as the new discovered drug combination NeuroHeal (NH)[4, 5]. NH was discovered using unbiased proteomic data, systems biology, and artificial neural networks from two models that represented pure regenerative and pure neurodegenerative conditions after peripheral nerve distal axotomy or root avulsion (RA) injuries, respectively. The data were used to build up bona fide state-specific molecular maps, and mathematical models were used to screen databases of drugs to identify putatively neuroprotective combinations. NH is a combination of acamprosate and ribavirin, two repurposed drugs with well-described pharmacokinetics and pharmacodynamics profiles that have no serious adverse effects
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