Melatonin

Melatonin (MLT), the main regulator of circadian rhythms primarily synthesized by the pineal gland, has antioxidant, anti-inflammatory, and anti-tumor activity. Receptor-dependent (MT1/MT2) and -independent melatonin signaling promotes mesenchymal stem cell (MSC) survival, therapeutic efficacy, and modulates their fate.
Melatonin upregulates osteogenic and chondrogenic differentiation and downregulates adipogenesis in MSCs through MT2 receptors and downstream MEK/ERK, BMP/Smad, and Wnt/β-catenin. It activates osteogenic genes while inhibiting PPARγ signaling, thus switching off adipogenesis. Melatonin, in chondrogenesis, decreases ROS production and MMPs to enhance cartilage repair in osteoarthritis. Importantly, it increases MSC survival in an oxidative stress by ERK1/2 and Bcl-2 activation and decreases senescence through upregulation of prion protein. Melatonin potentiates MSCs to treat ischemic, inflammatory, and infectious diseases by increasing angiogenesis and M2 macrophage polarization.
EVs derived from melatonin-primed MSCs (MT-EVs) further enhance these effects. MT-EVs are enriched in anti-inflammatory miRNAs and proteins that target NF-κB and PTEN/AKT pathways to decrease inflammation and promote tissue repair. MT-EVs have higher therapeutic efficacy than untreated EVs or MSCs alone in colitis, ischemia-reperfusion injury, diabetes, and neurodegenerative disease models and have the added advantage of being cell-free, avoiding potential tumorigenicity and immune rejection.

Fig. 1 Production and metabolism of Melatonin. (Feng Z Y.; et al. 2021)

Wang X et al. fabricated a novel multilayered compound nerve scaffold using electrospinning. The scaffold features an anti-adhesive outer layer of polycaprolactone (PCL) and an inner layer composed of an ECM-like alginate hydrogel loaded with Melatonin, enabling controlled drug release. This innovative scaffold was implanted into a challenged 15 mm rat sciatic nerve injury model. After a 16-week recovery period, the researchers conducted a comprehensive evaluation, including assessments of motor function via the Sciatic Functional Index, electrophysiology, target organ atrophy, nerve morphology, and molecular analysis of neural, inflammatory, oxidative stress, and angiogenic markers.
The intervention demonstrated significant success in improving the quality of nerve regeneration and functional recovery. Key results showed a marked increase in the sciatic functional index and nerve electrical conduction level. The controlled release of antioxidant melatonin effectively mitigated damage by reducing inflammation and oxidative stress in the reinnervated nerves. Furthermore, the scaffold facilitated angiogenesis, promoting neurite extension and axonal sprouting, which led to elevated fast-type myosin expression in the target gastrocnemius muscle.

Fig. 2 Fabrication of Cinnarizine microneedles. (Wang X.; et al. 2023)