Synergistic action of brain-derived neurotrophic factor and lens injury promotes retinal ganglion cell survival, but leads to optic nerve dystrophy in vivo

Abstract

Trauma or disease in the CNS often leads to neuronal death and consequent loss of functional connections. The idea has been put forward that strategies aimed at repairing the injured CNS involve stimulation of both neuronal survival and axon regeneration. We tested this hypothesis in the adult rat retinocollicular system by combining two strategies: (i) exogenous administration of brain-derived neurotrophic factor (BDNF), a potent survival factor for damaged retinal ganglion cells (RGCs) and (ii) lens injury, which promotes robust growth of transected RGC axons. Our results demonstrate that BDNF and lens injury interact synergistically to promote neuronal survival: 71% of RGCs were alive at 2 weeks after optic nerve injury, a time when only approximately 10% of these neurons remain without treatment. Intravitreal injection of BDNF, however, led to regeneration failure following lens injury. The effect of BDNF could not be generalized to other growth factors, as ciliary neurotrophic factor did not cause a significant reduction of lens injury-induced regeneration. Growth arrest in optic nerves treated with BDNF and lens injury correlated with the formation of hypertrophic axonal swellings in the proximal optic nerve. These swellings were filled with numerous vesicular bodies, disorganized neurofilaments and degenerating organelles. Our results demonstrate that: (i) increased neuronal survival does not necessarily lead to enhanced axon regeneration and (ii) activation of survival and growth pathways may produce axonal dystrophy similar to that found in neurodegenerative disorders including glaucoma, Alzheimer's disease and multiple sclerosis. We propose that loss of axonal integrity may limit neuronal recovery in the injured, adult CNS.

Gene therapy for retinal ganglion cell neuroprotection in glaucoma

“…55,56 Intriguingly, although the combination of BDNF and a preconditioning lens injury substantially enhanced RGC soma survival at 2 weeks post axotomy (71% survival compared with 44% in control eyes), this approach resulted in axonal dystrophy and regenerative failure. 57 Lens injury alone, on the other hand, promotes substantial axon regrowth in the order of 100-fold increase in the number of RGC axons that regenerate beyond the crush site, 58,59 an effect that has been partly attributed to oncomodulin, a novel macrophage-derived factor that promotes cAMP-dependent axonal regeneration. 60 Long-term studies have demonstrated that the pro-survival effect of BDNF on RGCs is temporary: it delays, but does not prevent, the onset of RGC death.…”

Boosting Central Nervous System Axon Regeneration by Circumventing Limitations of Natural Cytokine Signaling

“…[4][5][6] However, significant neuroprotection and axonal regeneration is achieved by inflammatory stimulation (IS), which can be induced in rodents, for example, by lens injury or intravitreal application of Pam 3 Cys or zymosan. [7][8][9][10][11][12][13] Besides several cell types of the innate immune response, IS also activates astrocytes and Müller cells to increase retinal expression of IL-6-type cytokines such as CNTF, LIF, and IL-6. 5,[14][15][16] Depletion of these cytokines using the respective genetic knockout compromises or even completely abolishes the regeneration-promoting effects of IS, thereby verifying their essential contribution to this approach.…”

Hyper-IL-6: a potent and efficacious stimulator of RGC regeneration

“…IS can be induced in rodents by lens injury or by intravitreal application of specific lens proteins, Pam 3 Cys, or zymosan. 12,[19][20][21][22][23][24] Besides several cell types of the innate immune response, IS activates retinal astrocytes and Müller cells to induce retinal expression of IL-6-type cytokines such as CNTF, LIF, and IL-6. 16,25,26 The essential contributions of each cytokine in mediating the neuroprotective and growth promoting effects of IS were verified by their depletion in respective genetic knockout mice, which compromised or even completely abolished the beneficial effects of IS.…”