Tamoxifen and Src kinase inhibitors as neuroprotective/neuroregenerative drugs after spinal cord injury

Abstract

Spinal cord injury (SCI) is a devastating condition that produces significant changes in the lifestyle of patients. Many molecular and cellular events are triggered after the initial physical impact to the cord. Two major phases have been described in the field of SCI: an acute phase and late phase. Most of the therapeutic strategies are focused on the late phase because this provides an opportunity to target cellular events like apoptosis, demyelination, scar formation and axonal outgrowth. In this mini-review, we will focus on two agents (tamoxifen and a Src kinase family inhibitor known as PP2) that have been shown in our laboratory to produce neuroprotective (increase cell survival) and/or regenerative (axonal outgrowth) actions. The animal model used in our laboratory is adult female rat (~250 g) with a moderate contusion (12.5 mm) to the spinal cord at the T10 level, using the MASCIS impactor device. Tamoxifen or PP2 was administered by implantation of a 15 mg pellet (Innovative Research of America, Sarasota, FL, USA) or by intraperitoneal injections (1.5 mg/kg, every 3 days), respectively, to produce a long-term effect (28 days). Tamoxifen and the Src kinase inhibitor, PP2, are drugs that in rats with a moderate spinal cord injury promote functional locomotor recovery, increase spared white matter tissue, and stimulate axonal outgrowth. Moreover, tamoxifen reduces the formation of reactive oxygen species. Therefore, these drugs are possible therapeutic agents that have a neuroprotective/regenerative activity in vertebrates with SCI.

17β-estradiol and tamoxifen protect mice from manganese-induced dopaminergic neurotoxicity

“…Our findings that TX exerts neuroprotection is corroborating with many previously reported neurotoxicity models, including methamphetamine-induced dopaminergic neurotoxicity in mice (Dluzen et al, 2001). TX exerts neuroprotection not only via ER-dependent mechanisms, but also the ER-independent mechanisms as shown that TX induced neuroprotection by activating antioxidant mechanisms in the methamphetamine toxicity mouse model (Kuo et al, 2003), ischemic rat model (Zhang et al, 2007), and the spinal cord injury rat model (Salgado et al, 2015).…”

The Role of Estrogen Receptors and Their Signaling across Psychiatric Disorders

“…Each has different properties and treatment effects, depending on the estrogen receptor subtypes, coactivators, and corepressors in the brain region. Reports show SERMs interact with ERα, Erβ, and, also, GPER and can activate both genomic and nongenomic cascades, such as cAMP/PKA, MAPK/ERKs, PI3K/Akt, and Wnt/β-catenin, which are major signaling pathways in our brain for cognition and neuroprotection [ 103 , 104 , 105 ]. However, different SERMs, for their distinct properties, result in different actions in our brains.…”

Elucidation of the mechanism of Zhenbao pills for the treatment of spinal cord injury by network pharmacology and molecular docking: A review

“…Phosphorylation of ephexin1 by Src kinase after spinal cord injury may be involved in the collapse of axon growth cones and inhibit axon generation, whereas the Src kinase inhibitor PP2 restores functional movement, increases preserved white matter tissue and stimulates axon growth in rats with moderate spinal cord injury. [ 58 ] It can be seen that the core targets TP53, AKT1, SRC, and CTNNB1 all play important roles in the development of spinal cord injury, and how quercetin, kaempferol, and ethyl isobutyrocholate, which have good docking results with the core targets, regulate the expression of these proteins will be further verified by experiments. In conclusion, the network pharmacology provides some ideas for the specific mechanism of Zhenbao pill in treating spinal cord injury.…”