“Combo” Multi-Target Pharmacological Therapy and New Formulations to Reduce Inflammation and Improve Endogenous Remyelination in Traumatic Spinal Cord Injury

Abstract

Spinal cord injury (SCI) is characterized by a cascade of events that lead to sensory and motor disabilities. To date, this condition is irreversible, and no cure exists. To improve myelin repair and limit secondary degeneration, we developed a multitherapy based on nanomedicines (NMeds) loaded with the promyelinating agent triiodothyronine (T3), used in combination with systemic ibuprofen and mouse nerve growth factor (mNGF). Poly-L-lactic-co-glycolic acid (PLGA) NMeds were optimized and loaded with T3 to promote sustained release. In vitro experiments confirmed the efficacy of T3-NMeds to differentiate oligodendrocyte precursor cells. In vivo rat experiments were performed in contusion SCI to explore the NMed biodistribution and efficacy of combo drugs at short- and long-term post-lesion. A strong anti-inflammatory effect was observed in the short term with a reduction of type M1 microglia and glutamate levels, but with a subsequent increase of TREM2. In the long term, an improvement of myelination in NG2-IR, an increase in MBP content, and a reduction of the demyelination area were observed. These data demonstrated that NMeds can successfully be used to obtain more controlled local drug delivery and that this multiple treatment could be effective in improving the outcome of SCIs.

Mesenchymal Stem Cell Transplantation: Neuroprotection and Nerve Regeneration After Spinal Cord Injury

“…Journal of Inflammation Research 2023:16 4766 and creating the final chronic stage scar. 31,[66][67][68] The body's natural process of glial scar formation, which initiates and initiates healing after SCI, but some researchers believe it to be one of the barriers to neuronal axon regeneration in the CNS (central nervous system). [69][70][71] Lesions grow and create cysts as the spinal cord injury progresses, leaving behind microcystic cavities from lingering necrotic or apoptotic cells that eventually form spinal cord cavities, inflicting permanent harm.…”

Synthetic Thyroid Hormone Receptor-β Agonists Promote Oligodendrocyte Precursor Cell Differentiation in the Presence of Inflammatory Challenges

“…In fact, our and other groups have demonstrated that OPC differentiation/maturation impairment in experimental allergic encephalomyelitis (EAE), an experimental model for MS, is accompanied by an increase in the T3-inactivating enzyme deiodinases 3 (D3) and dysregulation of TR mRNA expression [ 22 , 23 , 24 ]. We have also demonstrated that inflammation-induced tissue hypothyroidism can be partially overcome in vivo by exogenous T3 administration, observing that OPC differentiation and maturation are restored in T3-treated animals, resulting in improved myelin repair in EAE [ 22 ] and SCI [ 25 ]. This result has been confirmed by in vitro experiments in which we have demonstrated that inhibition of inflammation-induced D3 hyperactivity restores OPC differentiation [ 26 , 27 ].…”