Tamoxifen: an FDA approved drug with neuroprotective effects for spinal cord injury recovery

Abstract

Spinal cord injury (SCI) is a condition without a cure, affecting sensory and/or motor functions. The physical trauma to the spinal cord initiates a cascade of molecular and cellular events that generates a non-permissive environment for cell survival and axonal regeneration. Among these complex set of events are damage of the blood-brain barrier, edema formation, inflammation, oxidative stress, demyelination, reactive gliosis and apoptosis. The multiple events activated after SCI require a multi-active drug that could target most of these events and produce a permissive environment for cell survival, regeneration, vascular reorganization and synaptic formation. Tamoxifen, a selective estrogen receptor modulator, is an FDA approved drug with several neuroprotective properties that should be considered for the treatment of this devastating condition. Various investigators using different animal models and injury parameters have demonstrated the beneficial effects of this drug to improve functional locomotor recovery after SCI. Results suggest that the mechanism of action of Tamoxifen administration is to modulate anti-oxidant, anti-inflammatory and anti-gliotic responses. A gap of knowledge exists regarding the sex differences in response to Tamoxifen and the therapeutic window available to administer this treatment. In addition, the effects of Tamoxifen in axonal outgrowth or synapse formation needs to be investigated. This review will address some of the mechanisms activated by Tamoxifen after SCI and the results recently published by investigators in the field.

Keywords: anti-inflammatory; antioxidant; demyelination; estradiol; reactive gliosis; regeneration; selective estrogen receptor modulator; trauma.

Figure 1

Acute and chronic events initiated after spinal cord injury: anatomical and temporal events. Contusion or compression injury to the vertebral column causes a traumatic impact which breaks vertebrae and compresses the spinal cord initiating injury to the central nervous system (CNS). During the acute stages, the broken bones and the contusion will compress the spinal cord, causing mechanical damage which will lead to necrosis, axotomy, blood-brain barrier (BBB) disruption, vascular damage, ischemia, and reactive oxygen species generation. The BBB and vascular damage leads to the infiltration of immune cells into the spinal cord followed by a simultaneous inflammatory cascade. The initiation of these events will lead to apoptosis, demyelination, and reactive gliosis during the chronic stages after SCI. Reactive gliosis initiates a process of lesion encapsulation from the lesion epicenter and will begin to spread toward rostral and caudal levels while the injury extends. Immune cells enter a repair and clearance stage while astrocytic cells continue to design a glial scar that will become a cystic fluid filled cavity a month after the injury. In addition, a non-permissive environment for neurite extension will develop since axonal demyelination and astrocytes will produce repellent substances into the spinal cord that will block axonal regeneration, worsening the prognosis of recovery. Together, the inhibitory signals from the astrocytes, myelin, and pro-inflammatory cytokines create a non-permissive environment for axonal regeneration, neuronal survival, and locomotor recovery.

Figure 2

Multi-active properties of Tamoxifen administration after spinal cord injury. Contusion injury will initiate a primary and secondary cascade of events causing loss of sensory and motor function. Intervention with Tamoxifen will target multiple set of events from the acute to the chronic stages leading to a reduced cavity, better environment for cell survival, and improved functional locomotor response. Although the beneficial effects of this drug are recently well documented, questions still arise regarding the sex differences associated to treatment, the therapeutic window available, the effects of this drug in sensory systems recovery (including nociceptive sensation), the effects of this drug in the regenerative machinery after SCI, and the possibility of a combinatorial therapy to maximize the drug treatment effects.