The Synthetic Microneurotrophin BNN27 Affects Retinal Function in Rats With Streptozotocin-Induced Diabetes

Abstract

BNN27, a C17-spiroepoxy derivative of DHEA, was shown to have antiapoptotic properties via mechanisms involving the nerve growth factor receptors (tropomyosin-related kinase A [TrkA]/neurotrophin receptor p75 [p75]). In this study, we examined the effects of BNN27 on neural/glial cell function, apoptosis, and inflammation in the experimental rat streptozotocin (STZ) model of diabetic retinopathy (DR). The ability of BNN27 to activate the TrkA receptor and regulate p75 expression was investigated. BNN27 (2,10, and 50 mg/kg i.p. for 7 days) administration 4 weeks post-STZ injection (paradigm A) reversed the diabetes-induced glial activation and loss of function of amacrine cells (brain nitric oxide synthetase/tyrosine hydroxylase expression) and ganglion cell axons via a TrkA receptor (TrkAR)-dependent mechanism. BNN27 activated/phosphorylated the TrkA residue in the absence but not the presence of TrkAR inhibitor and abolished the diabetes-induced increase in p75 expression. However, it had no effect on retinal cell death (TUNEL cells). A similar result was observed when BNN27 (10 mg/kg i.p.) was administered at the onset of diabetes, every other day for 4 weeks (paradigm B). However, BNN27 decreased the activation of caspase-3 in both paradigms. Finally, BNN27 reduced the proinflammatory (TNFα and IL-1β) and increased the anti-inflammatory (IL-10 and IL-4) cytokine levels. These findings suggest that BNN27 has the pharmacological profile of a therapeutic for DR, since it targets both the neurodegenerative and inflammatory components of the disease.

Effects of BNN27, a novel C17-spiroepoxy steroid derivative, on experimental retinal detachment-induced photoreceptor cell death

“…Our data indicate that BNN27, probably by mimicking NGF action or cooperating with it, enhances the immune response of RD by increasing the numbers of infiltrating macrophages and microglia. Our results are, however, in contrast with two recent studies showing that BNN27 administration can reduce Iba-1 + microglia and pro-inflammatory cytokines in the cuprizone-induced experimental multiple sclerosis (MS) 29 or in the streptozotocin-induced experimental diabetic retinopathy (DR) 30 . At the same time, BNN27 increases anti-inflammatory cytokine, interleukin-10 and -4 (IL-10 and IL-4 respectively), levels in diabetic retinas 30 .…”

“…However, given the considerable clinical limitations of DHEA, due to its effects on the endocrine axis and its conversion to multiple androgen and estrogen metabolites 22 – 25 , several groups have synthesized a handful number of novel DHEA derivatives to mitigate this problem/effect 26 , 54 , 55 . Among them, to the best of our knowledge, only the spiro-analogs of DHEA (BNNs) have been tested and reported to have neuroprotective activity 26 , 27 , 29 , 30 , 56 , 57 . BNN27 can protect PC12 cells from serum deprivation-induced apoptosis 26 , 27 , can reduce TUNEL + cell death in superior cervical ganglia following NGF deprivation 27 and can also diminish caspase-3 mediated cell death in dorsal root ganglia of NGF null embryos 27 , in serum-deprived PC12 cells 27 and in cuprizone 29 - and diabetes 30 -induced apoptosis.…”

“…Among them, to the best of our knowledge, only the spiro-analogs of DHEA (BNNs) have been tested and reported to have neuroprotective activity 26 , 27 , 29 , 30 , 56 , 57 . BNN27 can protect PC12 cells from serum deprivation-induced apoptosis 26 , 27 , can reduce TUNEL + cell death in superior cervical ganglia following NGF deprivation 27 and can also diminish caspase-3 mediated cell death in dorsal root ganglia of NGF null embryos 27 , in serum-deprived PC12 cells 27 and in cuprizone 29 - and diabetes 30 -induced apoptosis. Ιn addition, and in contrast to polypeptidic neurotrophins that cannot cross the blood-brain barrier (BBB) 58 , the small lipophilic BNN27 can cross the BBB and can be detected in the mouse brain 30 minutes after intraperitoneal administration 28 .…”

“…BNN27 can rapidly enter the mouse central nervous system (CNS) 28 and can significantly diminish caspase-3 mediated cell death in the dorsal root ganglia of NGF null mice embryos 27 . Furthermore, BNN27 was able to protect mature oligodendrocytes in an animal model of multiple sclerosis (MS) 29 and reverse the diabetes-induced loss of immunoreactivity of retinal amacrine cells and ganglion cell axons’ markers in an experimental model of diabetic retinopathy (DR) 30 . Finally, BNN27 was neuroprotective in a co-culture of mouse motor neurons with human astrocytes from amyotrophic lateral sclerosis (ALS) patients, however, it did not improve several clinical characteristics of the SOD1 mouse model of the disease 31 .…”

TGR5 receptor activation attenuates diabetic retinopathy through suppression of RhoA/ROCK signaling

“…Increased inflammation in the retinas accelerates the progression of DR. 21 Our immunofluorescence assay indicated Figure 3A). Western blotting analysis further confirmed the findings and showed that treatments of diabetic rats with INT-777 significantly lowered GFAP expression in comparison with control group (Figure 3B).…”