Combinatorial Therapy Stimulates Long-Distance Regeneration, Target Reinnervation, and Partial Recovery of Vision After Optic Nerve Injury in Mice

Lima, Silmara de; Habboub, Ghaith; Benowitz, Larry I.

doi:10.1016/b978-0-12-407178-0.00007-7

Cited by 42 publications

(28 citation statements)

References 80 publications

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“…Further studies are required to determine the effects of glia–neuron interactions in various forms of retinal degeneration and during optic nerve and retinal regeneration. 41, 42, 43, 44, 45, 46 …”

Section: Discussionmentioning

confidence: 99%

Renin–angiotensin system regulates neurodegeneration in a mouse model of normal tension glaucoma

et al. 2014

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Glaucoma, one of the leading causes of irreversible blindness, is characterized by progressive degeneration of optic nerves and retinal ganglion cells (RGCs). In the mammalian retina, excitatory amino acid carrier 1 (EAAC1) is expressed in neural cells, including RGCs, and the loss of EAAC1 leads to RGC degeneration without elevated intraocular pressure (IOP). In the present study, we found that expressions of angiotensin II type 1 receptor (AT1-R) and Toll-like receptor 4 (TLR4) are increased in RGCs and retinal Müller glia in EAAC1-deficient (KO) mice. The orally active AT1-R antagonist candesartan suppressed TLR4 and lipopolysaccharide (LPS)-induced inducible nitric oxide synthase (iNOS) expressions in the EAAC1 KO mouse retina. Sequential in vivo retinal imaging and electrophysiological analysis revealed that treatment with candesartan was effective for RGC protection in EAAC1 KO mice without affecting IOP. In cultured Müller glia, candesartan suppressed LPS-induced iNOS production by inhibiting the TLR4-apoptosis signal-regulating kinase 1 pathway. These results suggest that the renin–angiotensin system is involved in the innate immune responses in both neural and glial cells, which accelerate neural cell death. Our findings raise intriguing possibilities for the management of glaucoma by utilizing widely prescribed drugs for the treatment of high blood pressure, in combination with conventional treatments to lower IOP.

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Section: Discussionmentioning

confidence: 99%

Renin–angiotensin system regulates neurodegeneration in a mouse model of normal tension glaucoma

et al. 2014

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“…Extrinsic factors that prevent axonal regeneration include inhibitory proteins associated with myelin [e.g., NogoA, myelin-associated glycoprotein (MAG), and oligodendrocyte-myelin glycoprotein (OMgp)], proteoglycans in the perineuronal net and glial scar [e.g., chondroitin sulfate proteoglycans (CSPGs) like aggrecan, versican, brevican, neurocan, NG2, and phosphacan], and molecules that repel axon growth during development which continue to be expressed in the mature CNS (e.g., semaphorins, ephrins, slits, netrins, robos, and Wnts) (reviewed in Benowitz and Yin, 2007; Benowitz and Carmichael, 2010; de Lima et al, 2012a; Omura et al, 2015). A summary of intrinsic and extrinsic factors affecting neural growth and inhibition is provided in Figure 2.…”

Section: Molecular Mechanisms Of Neural Repairmentioning

confidence: 99%

“…Some components of inflammation cause tissue damage and neuronal death (see The Biology of Neurological Injury section), while others promote cell survival, axon sprouting, and regeneration (Shetty and Turner, 1995; Yin et al, 2003; de Lima et al, 2012a; Kurimoto et al, 2013; Baldwin et al, 2015; reviewed in Benowitz and Popovich, 2011). Both oncomodulin, a macrophage-derived growth factor for RGCs, and injury-induced cytokine release appear to play a role in inflammation-induced axonal regeneration (Yin et al, 2006, 2009; Kurimoto et al, 2013).…”

Section: Molecular Mechanisms Of Neural Repairmentioning

confidence: 99%

Enhancing Nervous System Recovery through Neurobiologics, Neural Interface Training, and Neurorehabilitation

et al. 2016

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After an initial period of recovery, human neurological injury has long been thought to be static. In order to improve quality of life for those suffering from stroke, spinal cord injury, or traumatic brain injury, researchers have been working to restore the nervous system and reduce neurological deficits through a number of mechanisms. For example, neurobiologists have been identifying and manipulating components of the intra- and extracellular milieu to alter the regenerative potential of neurons, neuro-engineers have been producing brain-machine and neural interfaces that circumvent lesions to restore functionality, and neurorehabilitation experts have been developing new ways to revitalize the nervous system even in chronic disease. While each of these areas holds promise, their individual paths to clinical relevance remain difficult. Nonetheless, these methods are now able to synergistically enhance recovery of native motor function to levels which were previously believed to be impossible. Furthermore, such recovery can even persist after training, and for the first time there is evidence of functional axonal regrowth and rewiring in the central nervous system of animal models. To attain this type of regeneration, rehabilitation paradigms that pair cortically-based intent with activation of affected circuits and positive neurofeedback appear to be required—a phenomenon which raises new and far reaching questions about the underlying relationship between conscious action and neural repair. For this reason, we argue that multi-modal therapy will be necessary to facilitate a truly robust recovery, and that the success of investigational microscopic techniques may depend on their integration into macroscopic frameworks that include task-based neurorehabilitation. We further identify critical components of future neural repair strategies and explore the most updated knowledge, progress, and challenges in the fields of cellular neuronal repair, neural interfacing, and neurorehabilitation, all with the goal of better understanding neurological injury and how to improve recovery.

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“…21 Although separate mechanisms can induce optic nerve regeneration singly, combining different therapies allows for synergistic actions that activate the intrinsic growth state of RGCs and enables them to regenerate their axons to the full length of the optic nerve, across the optic chiasm, and into the brain, where they establish synapses in appropriate target zones and restore limited visual responses. 22,23 These treatments involve the induction of a limited inflammatory response in the eye, which increases the levels of oncomodulin and other growth factors, elevates intracellular Cyclic-adenosine-monophosphate (cAMP), and deletes the pten gene in RGCs. Although these approaches cannot be applied clinically, they indicate different approaches that may eventually be applied clinically.…”

Section: Changing Cellular Environment From One That Inhibits To One mentioning

confidence: 99%

“…Although these approaches cannot be applied clinically, they indicate different approaches that may eventually be applied clinically. 22 The optic nerve has been widely used to investigate factors that regulate axon regeneration in the mammalian CNS. Although RGCs show little capacity to regenerate their axons following optic nerve damage, studies show that some RGCs can regenerate axons through a segment of peripheral nerve grafted to the optic nerve.…”

Section: Changing Cellular Environment From One That Inhibits To One mentioning

confidence: 99%

Can mammalian vision be restored following optic nerve degeneration?

Kuffler¹

2016

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For most adult vertebrates, glaucoma, trauma, and tumors close to retinal ganglion cells (RGCs) result in their neuron death and no possibility of vision reestablishment. For more distant traumas, RGCs survive, but their axons do not regenerate into the distal nerve stump due to regeneration-inhibiting factors and absence of regeneration-promoting factors. The annual clinical incidence of blindness in the United States is 1:28 (4%) for persons >40 years, with the total number of blind people approaching 1.6 million. Thus, failure of optic nerves to regenerate is a significant problem. However, following transection of the optic nerve of adult amphibians and fish, the RGCs survive and their axons regenerate through the distal optic nerve stump and reestablish appropriate functional retinotopic connections and fully functional vision. This is because they lack factors that inhibit axon regeneration and possess factors that promote regeneration. The axon regeneration in lower vertebrates has led to extensive studies by using them as models in studies that attempt to understand the mechanisms by which axon regeneration is promoted, so that these mechanisms might be applied to higher vertebrates for restoring vision. Although many techniques have been tested, their successes have varied greatly from the recovery of light and dark perceptions to partial restoration of the optomotor response, depth perception, and circadian photoentrainment, thus demonstrating the feasibility of reconstructing central circuitry for vision after optic nerve damage in mature mammals. Thus, further research is required to induce the restoration of vision in higher vertebrates. This paper examines the causes of vision loss and techniques that promote transected optic nerve axons to regenerate and reestablish functional vision, with a focus on approaches that may have clinical applicability.

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Combinatorial Therapy Stimulates Long-Distance Regeneration, Target Reinnervation, and Partial Recovery of Vision After Optic Nerve Injury in Mice

Cited by 42 publications

References 80 publications

Renin–angiotensin system regulates neurodegeneration in a mouse model of normal tension glaucoma

Renin–angiotensin system regulates neurodegeneration in a mouse model of normal tension glaucoma

Enhancing Nervous System Recovery through Neurobiologics, Neural Interface Training, and Neurorehabilitation

Can mammalian vision be restored following optic nerve degeneration?

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