PI3K/akt, JAK/STAT and MEK/ERK pathway inhibition protects retinal ganglion cells via different mechanisms after optic nerve injury

Abstract

Recently we unexpectedly found that PI3K/akt, JAK/STAT and MEK/ERK pathway inhibitors enhanced retinal ganglion cell (RGC) survival after optic nerve (ON) axotomy in adult rat, a phenomenon contradictory to conventional belief that these pathways are pro-survival. In this study we showed that: (i) the RGC protection was pathway inhibition-dependent; (ii) inhibition of PI3K/akt and JAK/STAT, but not MEK/ERK, activated macrophages in the eye, (iii) macrophage removal from the eye using clodronate liposomes significantly impeded PI3K/akt and JAK/STAT inhibition-induced RGC survival and axon regeneration whereas it only slightly affected MEK/ERK inhibition-dependent protection; (iv) in the absence of recruited macrophages in the eye, inhibition of PI3K/akt or JAK/STAT did not influence RGC survival; and (v) strong PI3K/akt, JAK/STAT and MEK/ERK pathway activities were located in RGCs but not macrophages after ON injury. In retinal explants, in which supply of blood-derived macrophages is absent, MEK/ERK inhibition promoted RGC survival whereas PI3K/akt or JAK/STAT inhibition had no effect on RGC viability. However, MEK/ERK inhibition exerted opposite effects on the viability of purified adult RGCs at different concentrations in vitro, suggesting that this pathway may be bifunctional depending on the level of pathway activity. Our data thus demonstrate that inhibition of the PI3K/akt or JAK/STAT pathway activated macrophages to facilitate RGC protection after ON injury whereas the two pathways per se did not modulate RGC viability under the injury conditions (in the absence of the pathway activators). In contrast, the MEK/ERK pathway inhibition protected RGCs via macrophage-independent mechanism(s).

Role of Signal Transducer and Activator of Transcription 3 in Neuronal Survival and Regeneration

“…Neurochemical lesion with capsaicin, which destroys sensory neuron fibers but leaves their cell bodies intact [53], increases STAT3 phosphorylation in the DRG at 30 min, and in regenerating sensory fibers within the sciatic nerve at 6 h [34]. These findings are in agreement with the observation that mechanical lesion to the sciatic nerve increases P-STAT3 in spinal motor neurons and DRG during the regeneration period [77], and that P-STAT3 immunoreactivity decreases when [85] found that STAT3 is activated following optic nerve transection and that inhibition of JAK/STAT promoted, rather than inhibited, retinal ganglion cell survival and axon regeneration. Ganglion cell survival was accompanied by inhibition of macrophage recruitment into the eye, suggesting that JAK/STAT recruits macrophages to the site of injury, which exacerbates retinal injury, and that inhibition of JAK/STAT may promote regeneration by inhibiting macrophage recruitment.…”

“…These observations suggest that STAT3 plays an important role in neuronal repair after injury. In contrast, Luo et al [85] found that STAT3 is activated following optic nerve transection and that inhibition of JAK/STAT promoted, rather than inhibited, retinal ganglion cell survival and axon regeneration. Ganglion cell survival was accompanied by inhibition of macrophage recruitment into the eye, suggesting that JAK/STAT recruits macrophages to the site of injury, which exacerbates retinal injury, and that inhibition of JAK/STAT may promote regeneration by inhibiting macrophage recruitment.…”

Long Non-Coding RNA-MALAT1 Mediates Retinal Ganglion Cell Apoptosis Through the PI3K/Akt Signaling Pathway in Rats with Glaucoma

“…Moreover, the P13K/Akt signaling pathway can contribute to the neurite outgrowth of differentiated RGCs [40]. Therefore, this pathway is needed to inhibit the occurrence of apoptosis and promote axonal regeneration in both glaucoma and optic neuropathy [41, 42]. …”

Neuroprotective Effect of Ocular Hypotensive Drugs: Latanoprost/Timolol in Combination Are More Effective than Each as Monotherapy in RGC-5

“…8,31,32) We used LY294002 to inhibit Akt and to investigate the mechanism of protective effect of latanoprost/timolol in combination. LY294002 specifically inhibits PI3K.…”