Walking Again

It’s your first time taking the Honda Accord for a drive by yourself since getting your license. You decided to drive to school and back as the first day of school was approaching on Monday. You have practiced driving this route several times with your driving instructor, so you weren’t nervous. Before driving, you even put on some Rex Orange County tunes in the background. 

Following the normal route, you reach the red light right before the entrance to your school. You hear a rumble behind you and you check your rearview mirror. Before you can react, you enter an abyss of darkness, speckled with golden stars. Suddenly, you’re woken up by the sound of sliding glass doors and whispers. You’re blinking, trying to adjust to the scintillating fluorescent lights. The continued whispers cause you to try to adjust your body to see who is speaking, but you find yourself trapped. 

Spinal cord injuries are known to be debilitating and in many cases, limit the ability to walk. This article will investigate how a research group in Germany has enabled functional recovery in mice after spinal cord injury. Motor vehicle accidents are one of the leading causes of traumatic spinal cord injuries (SCIs), along with catastrophic falls and sports injuries. Traumatic SCIs result from forced impact, such as from a car accident or sports injury, whereas non-traumatic SCIs involve an infection or slow degeneration of bones [1]. 

Spinal Cord and Spinal Cord Injury

The spinal cord itself is a bundle of neurons and axons that go from the back of the brain and extend into the lower back. Axons are utilized to communicate information between skin, organs, muscles, and the brain [2]. They are a part of the neuron that carries signals known as action potentials up and down the spinal cord and the rest of the body [2]. These action potentials help the brain, which is where neurons are located, to send messages about voluntary movements, such as walking, to the legs [2]. The nervous system controls and acts as a communication interface between the central nervous system and peripheral nervous system. Therefore, the spinal cord and brain, which make up the central nervous system, control many parts of the body. There are thousands of axons that are bundled together into spinal nerves to create a connection between the muscles and the rest of the body [2].

Traumatic SCIs can lead to paraplegia, which is a loss of motor and sensory function in the lower extremities, or tetraplegia, loss of motor and sensory function in the lower extremities and arms [3]. When the spinal cord is injured, the area below where the cord was injured is affected [4]. Therefore, the higher the injury to the spinal cord, the greater the possibility for loss of motor function. Normally, the vertebrae, the bones that interlock to create the spinal column, protect the spinal cord, so when there is physical trauma, like that from a car accident, the vertebrae are shattered placing pressure on the spinal cord itself [3]. This pressure to the spinal cord can damage axons [4]. When these axons are damaged, action potentials cannot be sent. Therefore, there is no communication between the brain and spinal cord, ultimately resulting in paralysis [2, 4]. Axonal death or degeneration is part of inflammation from SCIs, along with neuronal cell death and macrophage accumulation. Macrophages are specialized cells that destroy harmful substances in the body and can initiate inflammation through the release of cytokines, which will be discussed later in this article [5]. Other factors may contribute to the extent of spinal cord injury, such as ruptured blood vessels causing harmful blood flow into the spinal cord and creating swelling [3]. This swelling may prevent adequate oxygenation delivery to neurons in the spinal cord and cause neurons to die [4].  

However, it is important to note that blocking the propagation of action potentials may contribute to spinal shock first, which is the temporary loss of spinal activity at the specific site of spinal injury and below. As a result, the extent and permanence of injuries cannot be fully determined until this spinal shock period is over, which is normally 24-48 hours [1]. Regardless of the level of damage obtained through a traumatic SCI, other medical complications may arise, such as pancreatitis, depression, and more [2]. This link to pancreatitis stems from studies showing that spinal cord injuries can create nervous system imbalances from the dysfunction of the sphincter of Oddi, which regulates bile flow from the liver to the small intestine [6]. Although SCI can impact mood regulation neurotransmitter mechanisms, the restrictions in everyday activities from a SCI is the likelier cause for depression [7, 8]. For these reasons, not only does paraplegia create a need for research in SCIs, but various infections and symptoms that can occur post-injury add to this need as well.

Bochum Research Group Findings

Luckily, the Bochum research group in Germany started exploring treatments for SCIs and was able to help regain function in the legs of a previously paralyzed mouse, ultimately allowing the mouse to walk again [9]. This team has been working on a designer cytokine, hyper-interleukin-6 (hIL-6). “Designer” means that the cytokine has been genetically engineered. Cytokines are cell signaling molecules that stimulate cells towards trauma or infection and are an integral part of the immune system, which regulates inflammation in order to defend the body from trauma and infection [10]. Other cytokines include interferons, which are defense proteins against viruses [10]. The Bochum team has been able to stimulate nerve cell regeneration in the visual system, however, they wanted to see how their research can apply to motor function. In their newly published study in January 2021, the team was able to have a paraplegic mouse start walking after delivery of hyper-interleukin-6 (hIL-6) to specific motor neurons in the sensorimotor cortex [9]. The sensorimotor cortex is the section of the brain that covers primary sensory and motor areas [11]. The delivery of hIL-6 to these motor neurons stimulated the regeneration of their respective axons within spinal cord motor tracts and allowed for the ability to walk again. According to the Basso Mouse Scale (BMS), which measures locomotion of mice based upon various open-field tests, mice that were injected with the hIL-6 had BMS scores that increased by 4, versus mice that were not injected with hIL-6 [9]. These hIL-6 mice were able to regain full hindlimb function, lift-off hind legs, followed by forward front-limb advancements, all of which are steps of walking [9]. On the cellular slide, these mice were able to start walking again due to the long-distance regeneration of axons [9] in serotonergic neurons, which are stimulated by and release of the neurotransmitter serotonin. In an SCI, there are disruptions of serotonergic projections into the spinal motor area that lead to a disruption of serotonin [12]. A previous experiment has also shown reduced levels of serotonin after SCIs [13]. Therefore, the regeneration of these serotonergic axons proves to be an important mechanism in order to gain the function of walking.

In the previous paragraph, hIL-6 has been mentioned several times in the context of motor neuron regeneration. It is important to note that hIL-6 is an abbreviation for hyper-interleukin-6. hIL-6 is a genetically engineered version of interleukin-6 (IL-6), which is a cytokine [9]. IL-6 is secreted by T cells and macrophages to activate immune responses during infection or after trauma [10]. These immune responses can be pro-inflammatory or anti-inflammatory, both of which are required for spinal cord regeneration [13]. Pro-inflammation allows for IL-6 to enhance the expression of other cytokines, while anti-inflammatory responses can reduce inflammation [13]. A study has shown that IL-6 triggers an inflammatory response after SCIs to enhance the response of other cytokines; however, blocking IL-6 had negative effects on SCI injuries [14]. This suggests that IL-6 is required for SCI regeneration for both types of immune responses and is a good target for SCI repair. Structurally, the IL-6 receptor, to which IL-6 itself attaches onto in order to be active, is made up of IL-6R and gp130 (glycoprotein 130). It was found to have limited regenerative effects in the spinal cord, as the IL-6 receptor is only expressed by a limited amount of cells (like macrophages or white blood cells) [15]. On the other hand, hIL-6 is a fusion protein of IL-6 and IL-6R through a peptide linker. The peptide linker allows hIL-6 to bind directly to gp130, which is an advantage as gp130 is expressed by all cells [15].  hIL-6 has greater regeneration potential than IL-6, as the gp130 allows hIL-6 to bind to more parts of the body. Even a previous study of umbilical cord stem cell transplantation treatments was unable to produce the same level of motor recovery as found with hIL-6 [16]. This greater regeneration potential was confirmed by the results (described in the previous paragraph) from the Bochum research group. 

The Bochum group’s research proves to be a groundbreaking discovery, as neurons of the mammalian central nervous system do not regenerate naturally. These novel findings can be used to help the quality of life of individuals who have been affected by motor vehicle accidents. The ability to recover motor function after spinal cord injury is a revolutionary mechanism that deserves to be popularized and further researched. Further research could lead to effective treatments for traumatic spinal cord injuries improving the function of an individual's life. 

References

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