Ibudilast Protects Retinal Bipolar Cells from Excitotoxic Retinal Damage and Activates the mTOR Pathway

Area of Science:

• Ophthalmology
• Neuroscience
• Pharmacology

Background:

• Ibudilast, a dual inhibitor of macrophage migration inhibitory factor (MIF) and phosphodiesterase (PDE), exhibits neuroprotective properties in various neurological conditions.
• Excitotoxic damage is a significant factor in retinal neuron loss, necessitating therapeutic strategies for neuroprotection.

Approach:

• A chick excitotoxic retinal damage model was employed to evaluate ibudilast's neuroprotective potential.
• Single-cell RNA sequencing (scRNA-seq) was utilized to analyze molecular changes in retinal cells following damage and treatment.
• Intravitreal ibudilast administration was assessed for efficacy and toxicity, with functional outcomes measured by electroretinography and structural integrity by spectral domain optical coherence tomography.

Key Points:

• scRNA-seq revealed upregulation of MIF, its receptors (CD74, CD44), and PDEs in retinal cells during damage.
• Ibudilast effectively protected inner nuclear layer neurons, preserved retinal structure, and improved ON bipolar cell function.
• Phosphodiesterase inhibition was critical for ibudilast's neuroprotective effect, as demonstrated by the ineffectiveness of a non-PDE inhibiting analogue (AV1013).
• Ibudilast treatment upregulated mTOR signaling in Müller glia and bipolar cells, though mTOR inhibition did not prevent cell death.

Conclusions:

• Ibudilast demonstrates significant neuroprotection for inner retinal neurons against excitotoxic injury.
• The study identified potential mechanisms including PDE inhibition, mTOR pathway modulation, and Müller glia-bipolar cell crosstalk.
• These findings support ibudilast's promise for clinical translation in treating retinal damage.