Ivermectin Promotes Peripheral Nerve Regeneration during Wound Healing

Abstract

Peripheral nerves have the capacity to regenerate due to the presence of neuroprotective glia of the peripheral nervous system, Schwann cells. Upon peripheral nerve injury, Schwann cells create a permissive microenvironment for neuronal regrowth by taking up cytotoxic glutamate and secreting neurotrophic signaling molecules. Impaired peripheral nerve repair is often caused by a defective Schwann cell response after injury, and there is a critical need to develop new strategies to enhance nerve regeneration, especially in organisms with restricted regenerative potential, such as humans. One approach is to explore mechanisms in lower organisms, in which nerve repair is much more efficient. A recent study demonstrated that the antiparasitic drug, ivermectin, caused hyperinnervation of primordial eye tissue in Xenopus laevis tadpoles. Our study aimed to examine the role of ivermectin in mammalian nerve repair. We performed in vitro assays utilizing human induced neural stem cells (hiNSCs) in co-culture with human dermal fibroblasts (hDFs) and found that ivermectin-treated hDFs promote hiNSC proliferation and migration. We also characterized the effects of ivermectin on hDFs and found that ivermectin causes hDFs to uptake extracellular glutamate, secrete glial cell-derived neurotrophic factor, develop an elongated bipolar morphology, and express glial fibrillary acidic protein. Finally, in a corresponding in vivo model, we found that localized ivermectin treatment in a dermal wound site induced the upregulation of both glial and neuronal markers upon healing. Taken together, we demonstrate that ivermectin promotes peripheral nerve regeneration by inducing fibroblasts to adopt a glia-like phenotype.

Ivermectin Prophylaxis Used for COVID-19: A Citywide, Prospective, Observational Study of 223,128 Subjects Using Propensity Score Matching

“…Additional actions of ivermectin described include agonism activity to the liver X receptor (LXR) and farnesoid X receptor (FXR), with multiple potential metabolic benefits [9,10]; neuronal regeneration [11,12], prevention of muscle hypoxia [13], and actions on specific sites, including interferon (INF) [14], nuclear factor-κB (NF-κB), lipopolysaccharide (LPS) [15], and Janus kinase/signal transducer and activator of transcription (JAK-STAT) and PAI-1 pathway [16,17]; generation of P21 activated kinase 1 (PAK-1) [18,19]; reduction of interleukin-6 (IL-6) levels [15]; allosteric modulation of P2X4 receptor [20]; inhibition of high mobility group box 1 (HMGB1) [21,22]; and suppression of mucus hypersecretion, diminished recruitment of immune cells, and production of cytokines in the lung [23]. Ivermectin is also described to induce T helper 1 cell (Th1)-type immune response against protozoan infections [24], and anti-coagulant action through binding to the S protein of some viruses [25].…”

Hyperosmolar Potassium Inhibits Myofibroblast Conversion and Reduces Scar Tissue Formation

“…29 The increase in blood vessel density could have further significance for the reinnervation of these tissues, as previous work has shown that endothelial cells secrete neurotrophic factors and are capable of directing targeted axonal growth in collagenbased systems. 17,30 In a separate study, where skin wounds were treated with ivermectin, ivermectin significantly altered fibroblast gene expression, resulting in increased dermal innervation and angiogenesis, 19 suggesting that KGluc-treated fibroblasts may also support an increased influx of blood vessels into the wound site. Further work is necessary to properly dissect the contributions of KGluc on enhancing angiogenesis; either through direct action on endothelial cells or through paracrine signaling with other cell types, such as through studying a model of ischemic tissue.…”

“…All animal protocols were approved by the Institutional Animal Care and Use Committee (IACUC) at Tufts University, and were conducted as previously reported. 19 Twelve week old female BALB/cJ mice (Jackson Laboratories, Bar Harbor, ME) were anesthetized with isofluorane and the dorsal surface was shaved and prepped for surgery. An 8 mm biopsy punch was utilized to make two round, full-thickness excisional wounds on either side of the spine.…”

Antibiotics with therapeutic effects on spinal cord injury: a review

“…Recent studies have shown that ivermectin could also be applied for cancer therapy as it induces apoptosis in cancerous cells of different malignancies, such as renal cell carcinoma and hematologic malignancies, through induction of mitochondrial dysfunction in these cells [83,84]. This agent also promotes nerve regeneration and wound healing by affecting fibroblasts and glial cell phenotypes [85]. Interestingly, it has been suggested that through affecting GABA receptors, ivermectin plays an antispastic role in patients with SCI [86].…”