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. 2023 Apr 3;133(7):e164223. doi: 10.1172/JCI164223

Figure 5. Neuroprotective effects of RTG on structural and functional levels.

Figure 5

(A) Illustration shows different RTG treatment regimens. (B) Prophylactic low-dose RTG treatment (1 mg/kg) attenuated motor deficits in chronic EAE (each n = 15). (C) Prophylactic and symptomatic (starting at an EAE score ≥2) high-dose RTG treatment (10 mg/kg; both, n = 5) attenuated EAE courses compared with SAL-treated controls (n = 6). Note that only prophylactic RTG treatment increased survival. (D) High-dose RTG treatment (n = 9) attenuated early EAE progression and increased survival relative to controls (n = 10). 4-AP treatment increased mortality (n = 8). (E) Memory function decline in SAL-treated EAE was prevented by RTG treatment (each, n = 8) compared with non-EAE mice (n = 6) in NOR testing 24 hours after habituation (dashed line indicates threshold for memory impairment). (F) OCT imaging (45 dpi EAE) showed a thinning of IRLs in SAL-treated mice (n = 18) that was prevented by prophylactic (n = 22) but not symptomatic (n = 9) RTG treatment. VEP latency delay (45 dpi EAE) was improved by prophylactic (n = 11) but not symptomatic (n = 5) RTG treatment compared with SAL treatment (n = 7). (G–I) Only prophylactic but not symptomatic RTG treatment prevented loss of Brn3a+ RGCs (G) and SMI312+ ON axons (H) and decreased Iba1+ cell infiltration (I) in EAE mice at 45 dpi (each n = 5). (J) Only prophylactic but not symptomatic RTG treatment prevented OL-Kir4.1 channel loss at 45 dpi in EAE (each n = 5), maintaining levels similar to those observed in non-EAE controls (n = 4). (K) Cartoon illustrates neuron-OL for the K+ shuttling mechanism during inflammatory demyelination. Enhanced (transient) neuronal Kv7 channel function augments axonal K+ efflux, counteracting neuronal hyperexcitability and contributing to neuroprotection and preservation of OL-Kir4.1 function. Scale bars: 50 μm (G); 20 μm (H–J). *P < 0.05 and **P < 0.01, by mixed-effects analysis with multiple comparisons (left) and, Mann-Whitney U test (right) (B); 2-way ANOVA (left), Kruskal-Wallis (middle), Mantel-Cox (right) (C and D); 2-way ANOVA (E and F); 1-way ANOVA (G–J).