Promoting Optic Nerve Regeneration in Adult Mice with Pharmaceutical Approach

Abstract

Our previous research has suggested that lack of Bcl-2-supported axonal growth mechanisms and the presence of glial scarring following injury are major impediments of optic nerve regeneration in postnatal mice. Mice overexpressing Bcl-2 and simultaneously carrying impairment in glial scar formation supported robust optic nerve regeneration in the postnatal stage. To develop a therapeutic strategy for optic nerve damage, the combined effects of chemicals that induce Bcl-2 expression and selectively eliminate mature astrocytes-scar forming cells-were examined in mice. Moodstabilizer, lithium, has been shown to induce Bcl-2 expression and stimulate axonal outgrowth in retinal ganglion cells in culture and in vivo. Moreover, astrotoxin (alpha-aminoadipate), a glutamate analogue, selectively kills astrocytes while has minimal effects on surrounding neurons. In the present study, we sought to determine whether concurrent applications of lithium and astrotoxin were sufficient to induce optic nerve regeneration in mice. Induction of Bcl-2 expression was detected in the ganglion cell layer (GCL) of mice that received a lithium diet in compared with control-treated group. Moreover, efficient elimination of astrocytes and glial scarring was observed in the optic nerve of mice treated with astrotoxin. Simultaneous application of lithium and astrotoxin, but not any of the drugs alone, induced robust optic nerve regeneration in adult mice. These findings further support that a combinatorial approach of concurrent activation of Bcl-2-supported growth mechanism and suppression of glial scarring is required for successful regeneration of the severed optic nerve in adult mice. They suggest a potential therapeutic strategy for treating optic nerve and CNS damage.

Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders

“…Lithium’s Bcl-2-dependent effects were later confirmed in vivo; in rats, lithium protects RGCs from partial optic nerve crush (Schuettauf et al, 2006). Co-application of lithium and astrotoxin, a glutamate analogue that selectively kills astrocytes with minimal effects on surrounding neurons, induces more robust optic nerve regeneration in adult mice (Cho & Chen, 2008). Lithium is also protective in cultured primary retinal neurocytes, where it promotes neurite outgrowth and DNA non-homologous end-joining following nutrient deprivation, an in vitro condition mimicking cell death in glaucoma (Zhuang et al, 2009).…”

Restoration of optic neuropathy

“…76 Lithium and other drugs have been treated as pharmaceutical approach to promote ON regeneration in animals. 77 To obtain further ON regeneration, those authors suggested to use lithium together with other drugs, citicoline, for instance, that mediate induction of permissive environment in the adult CNS.…”

Insight into astrocyte activation after optic nerve injury

“…BCL‐2 expression is turned off prenatally in the retinal neurons of mice, whereas BCL‐2 expression continues throughout life in fish and frogs and is upregulated during optic nerve regeneration (Chierzi et al, ). Several studies have shown that preventing reactive astrogliosis in the optic nerve and inducing the expression of Bcl‐2 results in the structural regeneration of the mouse optic nerve, including the re‐enervation of appropriate targets in the brain, although it was unclear whether vision was restored (Cho et al, ; Cho and Chen, ). The induction of BCL‐2 at P4 and the attenuation of reactive gliosis in mice result in rapid axonal regeneration over long distances.…”