👤 R L Nicol

Current treatment strategies for glaucoma, the leading cause of irreversible blindness, only target intraocular pressure (IOP) but not the underlying retinal ganglion cell degeneration. IOP management is not always effective, necessitating neuroprotective strategies. Lysophosphatidic acid (LPA) is an extracellular signaling molecule implicated in modulating inflammation. It exerts its signaling effects through its receptors (LPAR1-6). Here we test the efficacy of PIPE-791, an LPAR1-selective antagonist, in conferring neuroprotection and modulating neuroinflammation in glaucoma. A bead-induced rat ocular hypertension (OHT) model of glaucoma was used to test PIPE-791 (administered intraperitoneally at 3 mg/kg dosing). We monitored IOP through tonometry and evaluated PIPE-791's neuroprotective capacity by studying retinal ganglion cell survival using cell counting and its effects on retinal vasculature, immune cell numbers and cytokine profile. PIPE-791 had no effect on IOP in normotensive (NT) or OHT rat eyes. It also did not have any neuroprotective effect on retinal ganglion cell survival, nor did it normalize the changes in retinal vasculature observed in OHT retinas. Although PIPE-791 treatment increased microglial numbers in NT retinas, there was no effect in OHT retinas. Cytokine array profiling also revealed no significant effects for PIPE-791 on the cytokine changes between the NT and OHT retinas. These lack of changes could potentially be explained by the fact that LPAR1 protein levels are decreased in OHT retinas. Our data suggests that targeting LPAR1 through pharmacological means does not provide neuroprotection or modulate neuroinflammation favorably in glaucoma. Our study provides evidence that pharmacological targeting of LPAR1 as a potential therapeutic avenue in glaucoma may not be beneficial. Show less

Mitogen-activated protein kinase (MAPK) pathways couple intrinsic and extrinsic signals to hypertrophic growth of cardiomyocytes. The MAPK kinase MEK5 activates the MAPK ERK5. To investigate the potential involvement of MEK5-ERK5 in cardiac hypertrophy, we expressed constitutively active and dominant-negative forms of MEK5 in cardiomyocytes in vitro. MEK5 induced a form of hypertrophy in which cardiomyocytes acquired an elongated morphology and sarcomeres were assembled in a serial manner. The cytokine leukemia inhibitory factor (LIF), which stimulates MEK5 activity, evoked a similar response. Moreover, a dominant-negative MEK5 mutant specifically blocked LIF-induced elongation of cardiomyocytes and reduced expression of fetal cardiac genes without blocking other aspects of LIF-induced hypertrophy. Consistent with the ability of MEK5 to induce serial assembly of sarcomeres in vitro, cardiac-specific expression of activated MEK5 in transgenic mice resulted in eccentric cardiac hypertrophy that progressed to dilated cardiomyopathy and sudden death. These findings reveal a specific role for MEK5-ERK5 in the induction of eccentric cardiac hypertrophy and in transduction of cytokine signals that regulate serial sarcomere assembly. Show less