Neuroprotective effects of BDNF and GDNF in intravitreally transplanted mesenchymal stem cells after optic nerve crush in mice

Recently, we showed that matrix metalloproteinase-12 (MMP-12) is highly expressed in microglia and myeloid infiltrates, which are presumably involved in blood–brain barrier (BBB) leakage and subsequent neuronal cell death that follows status epilepticus (SE). Here, we assessed the effects of a hydroxypyrone-based inhibitor selective for MMP-12 in the pilocarpine-induced SE rat model to determine hippocampal cell survival. In the hippocampus of rats treated with pilocarpine, intra-hippocampal injections of the MMP-12 inhibitor protected Cornu Ammonis 3 (CA3) and hilus of dentate gyrus neurons against cell death and limited the development of the ischemic-like lesion that typically develops in the CA3 stratum lacunosum-moleculare of the hippocampus. Furthermore, we showed that MMP-12 inhibition limited immunoglobulin G and albumin extravasation after SE, suggesting a reduction in BBB leakage. Finally, to rule out any possible involvement of seizure modulation in the neuroprotective effects of MMP-12 inhibition, neuroprotection was also observed in the retina of treated animals after optic nerve crush. Overall, these results support the hypothesis that MMP-12 inhibition can directly counteract neuronal cell death and that the specific hydroxypyrone-based inhibitor used in this study could be a potential therapeutic agent against neurological diseases/disorders characterized by an important inflammatory response and/or neuronal cell loss.

Download Full-text

Neuroprotective Properties of Dimethyl Fumarate Measured by Optical Coherence Tomography in Non-inflammatory Animal Models

Frontiers in Neurology ◽

10.3389/fneur.2020.601628 ◽

2021 ◽

Vol 11 ◽

Author(s):

Michael Dietrich ◽

Christina Hecker ◽

Milad Nasiri ◽

Sogol Samsam ◽

Andrea Issberner ◽

...

Keyword(s):

Optical Coherence Tomography ◽

Optic Nerve ◽

Animal Models ◽

Retinal Degeneration ◽

Dimethyl Fumarate ◽

Age Related Macular Degeneration ◽

Optic Nerve Crush ◽

Optical Coherence ◽

Neuroprotective Effects ◽

Nerve Crush

While great advances have been made in the immunomodulatory treatment of multiple sclerosis (MS), there is still an unmet need for drugs with neuroprotective potential. Dimethyl fumarate (DMF) has been suggested to exert both immunomodulatory and neuroprotective effects in MS. To investigate if DMF has neuroprotective effects independent of immunomodulation we evaluated its effects in the non-inflammatory animal models of light-induced photoreceptor loss and optic nerve crush. This might also reveal applications for DMF besides MS, such as age related macular degeneration. Retinal neurodegeneration was longitudinally assessed by in vivo retinal imaging using optical coherence tomography (OCT), and glutathione (GSH) measurements as well as histological investigations were performed to clarify the mode of action. For light-induced photoreceptor loss, one eye of C57BL/6J mice was irradiated with a LED cold light lamp while for optic nerve crush the optic nerve was clamped behind the eye bulb. The other eye served as control. GSH was measured in the optic nerve, choroid and retina and immunohistological staining of retinal microglia (Iba1) was performed. Mice were treated with 15 or 30 mg DMF/kg bodyweight or vehicle. While no protective effects were observed in optic nerve crush, in the light-induced retinal degeneration model DMF treatment significantly reduced retinal degeneration. In these mice, GSH levels in the retina and surrounding choroid were increased and histological investigations revealed less microglial activation in the outer retinal layers, suggesting both antioxidant and anti-inflammatory effects.

Download Full-text