Abstract
Eye-drop recombinant human nerve growth factor (ed-rhNGF) has proved to recover the retina and optic nerve damage in animal models, including the unilateral optic nerve crush (ONC), and to improve visual acuity in humans. These data, associated with evidence that ed-rhNGF stimulates the brain derived neurotrophic factor (BDNF) in retina and cortex, suggests that NGF might exert retino-fugal effects by affecting BDNF and its receptor TrkB. To address these questions, their expression and relationship with the GABAergic and glutamatergic transmission markers, GAD65 and GAD67, vesicular inhibitory amino acid transporter (VGAT), and vesicular glutamate transporters 1 and 2 (VGLUT-1 and VGLUT-2) were investigated in adult ONC rats contralateral and ipsilateral visual cortex (VCx). Ed-rhNGF recovers the ONC-induced alteration of GABAergic and glutamatergic markers in contralateral VCx, induces an upregulation of TrkB, which is positively correlated with BDNF precursor (proBDNF) decrease in both VCx sides, and strongly enhances TrkB+ cell soma and neuronal endings surrounded by GAD65 immuno-reactive afferents. These findings contribute to enlarging the knowledge on the mechanism of actions and cellular targets of exogenously administrated NGF, and suggest that ed-rhNGF might act by potentiating the activity-dependent TrkB expression in GAD+ cells in VCx following retina damage and/or ONC.
Highlights
The neurotrophin nerve growth factor (NGF), as well as its family-related brainderived neurotrophic factor (BDNF) are considered fundamental during the development of the nervous system and to maintaining the functional integrity of the nervous tissue in adults
No differences were found by comparing the levels of glutamate transporters in the two visual cortex (VCx) sides in CTRL rats, the mean value between the two areas was considered for the comparative analysis
A further increase was found in optic nerve crush (ONC)+rhNGF rats where the VGLUT-1 level in the right VCx was about 200% and 140% of the levels detected in CTRL (p < 0.001) and ONC rats (p < 0.001), respectively
Summary
The neurotrophin nerve growth factor (NGF), as well as its family-related brainderived neurotrophic factor (BDNF) are considered fundamental during the development of the nervous system and to maintaining the functional integrity of the nervous tissue in adults. Neuroprotective and regenerative effects of ed-NGF on the retina and optic nerve have been demonstrated in adult rats with unilateral optic nerve crush (ONC), a well-described model of optic neuropathy [14,15,16] By affecting both anterograde and retrograde transport through the optic nerve, ONC is characterized by a neurotrophin support deprivation, which results in retina damage [15] and in a diffuse degeneration in the primary visual areas contralateral to the lesioned nerve, effects on the ipsilateral side are reported [17,18,19,20,21,22,23]. A decline of neuronal activity [25], early genes expression [26], and neurotransmitters, such as glutamate and c-aminobutyric acid (GABA) [27], are observable starting from the second week after retina or optic nerve lesion
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