TRPA1 deficiency is protective in cuprizone-induced demyelination-A new target against oligodendrocyte apoptosis

Abstract

Multiple sclerosis is a chronic inflammatory, demyelinating degenerative disease of the central nervous system. Current treatments target pathological immune responses to counteract the inflammatory processes. However, these drugs do not restrain the long-term progression of clinical disability. For this reason, new therapeutic approaches and identification of novel target molecules are needed to prevent demyelination or promote repair mechanisms. Transient Receptor Potential Ankyrin 1 (TRPA1) is a nonselective cation channel with relatively high Ca permeability. Its pathophysiological role in central nervous system disorders has not been elucidated yet. In the present study, we aimed to assess the distribution of TRPA1 in the mouse brain and reveal its regulatory role in the cuprizone-induced demyelination. This toxin-induced model, characterized by oligodendrocyte apoptosis and subsequent primary demyelination, allows us to investigate the nonimmune aspects of multiple sclerosis. We found that TRPA1 is expressed on astrocytes in the mouse central nervous system. Interestingly, TRPA1 deficiency significantly attenuated cuprizone-induced demyelination by reducing the apoptosis of mature oligodendrocytes. Our data suggest that TRPA1 regulates mitogen-activated protein kinase pathways, as well as transcription factor c-Jun and a proapoptotic Bcl-2 family member (Bak) expression resulting in enhanced oligodendrocyte apoptosis. In conclusion, we propose that TRPA1 receptors enhancing the intracellular Ca concentration modulate astrocyte functions, and influence the pro or anti-apoptotic pathways in oligodendrocytes. Inhibition of TRPA1 receptors might successfully diminish the degenerative pathology in multiple sclerosis and could be a promising therapeutic target to limit central nervous system damage in demyelinating diseases. GLIA 2016;64:2166-2180.

Investigation of Cuprizone-Induced Demyelination in mGFAP-Driven Conditional Transient Receptor Potential Ankyrin 1 (TRPA1) Receptor Knockout Mice

“…Feeding mice with cuprizone leads to a well-reproducible demyelination of the corpus callosum as well as other subcortical and cortical brain areas by inducing oligodendrocyte apoptosis and a secondary activation of astrocytes and microglia [15,16,[18][19][20][21]. We have revealed that demyelination of the corpus callosum was significantly reduced in TRPA1 receptor gene-deleted mice [22,23]. Based on our data we have assumed that TRPA1 receptors localized on astrocytes may influence the astrocyte-oligodendrocyte crosstalk.…”

“…Activation of these receptors on the astrocytes increases the intracellular Ca 2+ concentration and subsequent release of mediators. Astrocyte-derived signaling molecules may contribute to the apoptosis of oligodendrocytes by promoting the proapoptotic p38-MAPK pathway resulting in c-Jun activation [22]. We have also shown that TRPA1 deficiency did not affect the number of oligodendrocyte precursor cells (OPCs) during cuprizone treatment.…”

Neurotoxic Agent-Induced Injury in Neurodegenerative Disease Model: Focus on Involvement of Glutamate Receptors

“…It is particularly used to induce multiple sclerosis-like syndromes. In the experimental animal model, it has shown to cause demyelination, oxidative stress, neuroinflammation, and apoptosis leading to neuronal cell death (Gudi et al, 2014; Zimmermann et al, 2014; Slowik et al, 2015; Sághy et al, 2016; Ragerdi Kashani et al, 2017; Sanadgol et al, 2017). In the cuprizone model of demyelination, the NMDARs specific antagonist MK-801 delays remyelination.…”

Protecting Oligodendrocytes by Targeting Non-Glutamate Receptors as a New Therapeutic Strategy for Ischemic Stroke

“…TRPA1 antagonists may serve as a new therapeutic avenue for mitigating damage in ischemic stroke. In fact, the results from Saghy et al [26] showed that TRPA1 also regulates mitogen-activated protein kinase pathways, the transcription factor, c-Jun, and expression of a proapoptotic Bcl-2 family member, Bak, which increase OLG apoptosis. Inhibiting TRPA1 receptors may successfully diminish the degenerative pathology in demyelinating diseases [26].…”

“…In fact, the results from Saghy et al [26] showed that TRPA1 also regulates mitogen-activated protein kinase pathways, the transcription factor, c-Jun, and expression of a proapoptotic Bcl-2 family member, Bak, which increase OLG apoptosis. Inhibiting TRPA1 receptors may successfully diminish the degenerative pathology in demyelinating diseases [26]. Apart from OLG death, TRPA1 also contributes to neuronal death in retinal ischemia [27], and plays a crucial role in regulating astrocyte/microglia-derived inflammation [28,29].…”