Abstract
In addition to its role as an endocrine messenger, growth hormone (GH) also acts as a neurotrophic factor in the central nervous system (CNS), whose effects are involved in neuroprotection, axonal growth, and synaptogenic modulation. An increasing amount of clinical evidence shows a beneficial effect of GH treatment in patients with brain trauma, stroke, spinal cord injury, impaired cognitive function, and neurodegenerative processes. In response to injury, Müller cells transdifferentiate into neural progenitors and proliferate, which constitutes an early regenerative process in the chicken retina. In this work, we studied the long-term protective effect of GH after causing severe excitotoxic damage in the retina. Thus, an acute neural injury was induced via the intravitreal injection of kainic acid (KA, 20 µg), which was followed by chronic administration of GH (10 injections [300 ng] over 21 days). Damage provoked a severe disruption of several retinal layers. However, in KA-damaged retinas treated with GH, we observed a significant restoration of the inner plexiform layer (IPL, 2.4-fold) and inner nuclear layer (INL, 1.5-fold) thickness and a general improvement of the retinal structure. In addition, we also observed an increase in the expression of several genes involved in important regenerative pathways, including: synaptogenic markers (DLG1, NRXN1, GAP43); glutamate receptor subunits (NR1 and GRIK4); pro-survival factors (BDNF, Bcl-2 and TNF-R2); and Notch signaling proteins (Notch1 and Hes5). Interestingly, Müller cell transdifferentiation markers (Sox2 and FGF2) were upregulated by this long-term chronic GH treatment. These results are consistent with a significant increase in the number of BrdU-positive cells observed in the KA-damaged retina, which was induced by GH administration. Our data suggest that GH is able to facilitate the early proliferative response of the injured retina and enhance the regeneration of neurite interconnections.
Highlights
Neurotrophic factors, tissue organization, and microenvironmental dynamics are key elements to understand adult neurogenesis and neuroregeneration [1,2]
Histological analysis of the retinal tissues stained with hematoxylin revealed that, in comparison to the control, important morphological changes occurred in all treatment groups; the most evident cytostructural modification occurred in KA-damaged groups where a severe disruption of cellular organization in several retinal layers was observed (Figure 1B)
Morphometric analysis, performed by measuring changes in layer thickness, showed that KA caused a significant decrease in retinal thickness (from photoreceptors (PR) layer to ganglion cell layer (GCL) (63.1 ± 3.4 μm; p < 0.0001), as well as a drastic reduction in the thickness of the inner plexiform layer (IPL) (51.6 ± 2.01 μm; p < 0.0001) and the inner nuclear layer (INL) (29.5 ± 1.6 μm; p < 0.0001) (Figure 1C–E), when compared to their respective controls
Summary
Neurotrophic factors, tissue organization, and microenvironmental dynamics are key elements to understand adult neurogenesis and neuroregeneration [1,2]. A common ground in vertebrate species is the potential capacity of organisms to induce retinal neuroregeneration after injury. The retinal pigment epithelium, and the ciliary marginal zone are a common potential source of neural progenitors in the retina, though the efficiency and regulation of these neurogenic niches—cellular interactions, signaling pathways, and local factors—may differ among species [10,11]. Neuroregenerative process does not restore neural function through cell replacement and functional neurogenesis has not been described yet [10,14] This model allows for the study of the signals that trigger Müller cell de-differentiation and the factors which may prevent functional recovery in response to injury [15]
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