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.

Keywords: PP2; Src kinase; neuroprotection; regeneration; tamoxifen; trauma.

Figure 1

Estradiol and tamoxifen (TAM) improve the behavioral performance of injured rats in the beam crossing test. Ovariectomized rats were treated with estradiol (3 mg) or tamoxifen (15 mg), either by silastic tubing or commercial pellets, respectively, 1 week prior to spinal cord injury. The injured rats were tested weekly and the number of rats that crossed the narrow beam was analyzed with analysis of varivance followed by Bonferroni post hoc test. Results demonstrated a significance difference between control (n = 13) and treated (estradiol: n = 12; TAM: n = 10) animals (*P < 0.0016).

Figure 2

Neuroprotective and neurodegenerative effects of TAM and PP2 in spinal cord injury. TAM (A) and PP2 (B) are drugs that in a moderate spinal cord injury act as neuroprotective and neuroregenerative agents that promote functional locomotor recovery and increase spared white matter tissue. Additionally, TAM plays an important role as superoxide scavenger. ↑ Increase; ↓ decrease; TAM: tamoxifen; PP2: Src kinase inhibitor; ROS: reactive oxygen species; NF: neurofilament; NeuN: neuronal transcription factor; 5HT: 5-hydroxytryptamine; BBB: blood brain barrier; GAP-43: growth associated protein 43; GFAP: glial fibrillary acidic protein.