This ongoing “Healing Options” series has periodically discussed various, commonly consumed substances, which may provide some neuroprotection when administered soon after spinal cord injury (SCI). Examples include the cholesterol-lowering statin drugs (e.g., Lipitor), painkiller ibuprofen, herbal remedy Ginkgo biloba, sleep-inducing hormone melatonin, cancer-fighting quercetin found in foods, and the ubiquitous supplement vitamin E.  This update specifically discusses another potential neuroprotectant with extensive human use, specifically the hormone estrogen.

Estrogen

Although estrogen exerts many physiological effects in both women and men, it is most well known as the female sex hormone. In women, estrogen is primarily produced by the ovaries. It regulates the female estrous or reproductive cycle, and promotes the development of secondary sexual characteristics.

In men the hormone is produced at a much lower level by the testis, and plays a key role in testicular function. In aging men, elevated estrogen levels are associated with an increased risk of stroke, heart disease, and prostate problems, and low levels with osteoporosis and bone fractures.

Estrogen derivatives are a key component of many oral contraceptives and have been used for postmenopausal hormone-replacement therapy. Although estrogen’s reproductive roles receive the most attention, this potent, multiactive hormone can influence diverse physiological processes. As such, it theoretically has broad therapeutic potential much beyond its more obvious roles, including as a possible protective agent after neurotrauma.

Estrogen & SCI

The SCI neuroprotective possibilities have been extensively studied by Dr. Naren Banik and colleagues at the Medical University of South Carolina using animal models of SCI, as well as cultures of neuronal cells.

Animal Studies: SCI was produced by accessing the thoracic spinal cord of rats through laminectomy and dropping a weight on the exposed cord. Essentially, this is an experimental version of the sort of contusion injury experienced by many individuals with SCI. The rats were then treated intravenously with estrogen 15 minutes and 24 hours after injury, and, for the next five days, with a single daily dose injected into the body cavity. Recovery of locomotor function was followed for six weeks, and the amount of improvement observed compared to similarly injured control rats which received no estrogen.

Locomotion was assessed using the BBB scale, a commonly used animal test which measures recovery of hind-limb function on a scale from 0 (no hind-limb movement) to 21 (normal walking). At the end of the observation period, the average BBB score for the estrogen-treated rats was 13 compared to nine for the controls. Functionally, these statistically significant differences mean that when compared to controls, the estrogen-treated rats were better able to support their body weight, make weight-supported steps, and coordinate hindlimb/forelimb stepping. The investigators concluded that “estrogen treatment significantly increased the locomotor function in the injured animals over the 42-day postinjury period…”

Possible Mechanisms: These investigators and others have devoted much effort trying to understand the specific biological mechanisms by which estrogen mediates neuroprotection. The damage-spreading, pathophysiological cascade after the initial physical insult is extraordinarily complex and is the reason why SCI has been difficult to understand at a molecular level. Given this complexity, as well as estrogen’s increasingly documented, powerful multifaceted role in the body, there are many possible biological systems in which the hormone could target. Some possibilities are briefly highlighted below. It is emphasized, however, that these are often complex interlinked and interdependent processes.

1) Calcium Influx: Neuronal conduction depends upon the right balance of calcium ions between the cell inside and outside. Normally, there is a lot of calcium outside of the neuron and relatively little inside.  Injury disrupts the equilibrium, allowing excessive calcium to flow into the cell. This influx initiates a neural-destructive cascade that damages other neurons.  By inhibiting the calcium influx into the cells, estrogen lessens this damaging-perpetuating cascade.

 2) Apoptosis: Cells at the injury site die of necrosis, while cells surrounding the site often die from apoptosis,. As a crude analogy, necrotic cell death is like a quick death from being shot and apoptotic cell death is more like a lingering death from cancer. Because apoptosis is potentially reversible, treatments that turn this process around should help minimize postinjury cell degeneration. By modulating the activity of certain enzymes that promote postinjury apoptosis, estrogen slows down degeneration.

3) Excitotoxicity: Routinely, certain amino acids, like glutamate, are released from a pre-synaptic neuron and flow to a nearby post-synaptic neuron, promulgating the nerve impulse. However, after injury, cells burst, releasing too much glutamate. Through interactions with receptors on neighboring cells, this excessive glutamate will initiate a neurotoxic biochemical cascade. Estrogen protects against this excitotoxicity-caused cell death.

4) Edema: Fluid accumulation at the injury site creates damaging edema swelling. Estrogen-treated rats exhibit less edema.

5) Inflammation: Inflammatory cells infiltrate into the lesion area, which promotes secondary cell death. Estrogen treatment lessens infiltration.

6) Myelin: The fatty insulation surrounding axons, myelin enables neurons to propagate a signal. SCI often results in axonal demyelination, another process which is attenuated by estrogen.

7) Blood Flow: Injury compromises regeneration-promoting blood flow, contributing to secondary cell death. Estrogen promotes the growth of new blood vessels (i.e. angiogenesis), enhancing postinjury blood flow.

8) Antioxidant: After the initial mechanical injury in SCI, free-radicals are generated. Called lipid peroxidation, these free radicals can steal electrons from neighboring cell membranes, resulting in further cell death. A potent antioxidant, estrogen may reduce free-radical-induced oxidative stress.

Given these findings and the fact that women have much higher levels of estrogen than men, it is interesting to note that studies suggest that women recover more function after neurotrauma.

Need for New Treatment Options

Before you grab your wife’s birth-control pills, remember estrogen’s promising neuroprotective potential is based on animal studies often using high dosing, which doesn’t necessarily translate into human efficacy. Nevertheless, we clearly need to develop new SCI-treatment options. Since the 1990s, the big tamale for treating acute injury has been high-dose methylprednisolone (MP), a synthetic glucocorticoid steroid. Unfortunately, this therapeutic tamale is causing heartburn for a growing number of scientists.

Although several large clinical trials sponsored by the National Institutes of Health suggested that MP preserves function, more recent studies are questioning these conclusions. For example, emerging research suggests that high-dose MP therapy damages muscles and that functional improvement attributed to MP may merely be due to the recovery of muscle damage caused by the drug itself. In addition, a recent Japanese study indicates that MP-treated patients actually had less improvement than non-MP-treated patients.

Adapted from article appearing in April 2011 Paraplegia News (For subscriptions, call 602-224-0500) or go to www.pn-magazine.com. 

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