There are at least 25 well-established secondary injury mechanisms that can occur within minutes, weeks and months following a SCI (Oyinbo, 2011). Of these, the mechanisms that are most targeted for pharmaceutical intervention are reviewed below.
Inflammation occurs within the first minutes of a SCI and can persist for weeks or even months. It is predominantly caused by immune cells releasing reactive oxygen species and pro-inflammatory cytokines. The presence of immune cells can initially be advantageous because they remove cellular debris that resulted from the original injury in an effort to make room for new neurons to grow. Excessive and/or chronic inflammation, however, can lead to exacerbation and damage of surrounding healthy tissue (Allison & Ditor, 2015).
Vascular Secondary Injuries: Hemorrhage and Ischemia
SCI leads to local haemorrhaging and associated cell death, especially in the grey matter. Capillaries and venules at the injury site can experience a sudden reduction in blood flow and this ischemia can continue to worsen over several hours post injury. Ischemia is arguably the biggest determinant of the degree of secondary injury, as it often extends beyond the spinal cord and negatively affects perfusion and oxygenation in surrounding tissues, causing permanent damage (Amar & Levy, 1999). Hemorrhage can promote ischemia (Wallace et al. 1986); in turn ischemia can promote edema of the spinal cord (Tator, 1998) and production of reactive oxygen species (Lewen et al. 2000).
An additional biochemical outcome of secondary injury is an increase in cellular levels of calcium ions. To pass an electrical signal between neurons, neurotransmitters must be released from one synapse and bind to receptors on the neighbouring synapse. This release of neurotransmitters is regulated by calcium ions moving through calcium channels. The N-methyl-D-aspartate (NMDA) receptor is a calcium channel that, when open, allows electrical signals to transfer between neurons in the spinal cord. The receptor is only open when it is bound with glutamate (Guzmán-Lenis et al. 2009). The initial spinal cord trauma and subsequent ischemia produce an accumulation of glutamate around the injury site (Amar & Levy, 1999). Excitotoxicity occurs when excessive glutamate causes overstimulation of the NMDA receptor, allowing high levels of calcium ions into the neighbouring cells. The influx of calcium activates a series of destructive enzymes, including phospholipases that go on to damage the phospholipid cell membrane and proteases thereby destroying proteins. Over time, neuron cells become damaged and die. Other negative effects of excitotoxicity include edema of the spinal cord and the production of reactive oxygen species (Grossman et al. 2014).
During secondary injury, toxic oxygen free radicals are produced from excitotoxicity, mitochondrial dysfunction and the oxidative stress resulting from ischemia. These reactive oxygen species, as well as other free radicals created from the injury, react with proteins and lipids in nerve cells (Christie et al. 2008). Lipid peroxidation is a major cause of secondary nerve damage because the phospholipid membranes of neurons become oxidized and rupture (Kavanagh & Kam, 2001).
Apoptosis of neurons seems to be largely a result of high calcium levels in the cells during excitotoxicity, as well as the interaction with reactive oxygen species and inflammation. Taken together, these processes can activate signaling cascades leading to programmed cell death of nerve cells and surrounding tissue cells (Oyinbo, 2011).
Axon Demyelination and Degeneration
Neurons that survive the initial mechanical injury are still at risk of death from axon demyelination for many weeks post SCI (Liu et al. 1997). The initial injury as well as subsequent inflammation (Waxman, 1989) and excitotoxicity (Casha et al. 2001) destroys the surviving neurons’ oligodendrocytes, which are critical to neuron protection because they are the glial cells that form the myelin sheath around axons in the central nervous system. Demyelination leaves axons unprotected and vulnerable to degeneration and apoptosis from reactive oxygen species and inflammatory cytokines.
An intact spinal cord is required for proper autonomic nervous system (ANS) function and thus cardiovascular stability. The ANS is comprised of two opposing systems, the sympathetic nervous system (SNS) and parasympathetic nervous system (PNS), which interact to regulate various functions including heart rate (HR), blood pressure (BP) and vagal tone. Changes in cardiovascular function are lesion-dependent, with high-level injuries (T6 or above) contributing to significant SNS dysfunction and resulting in the greatest degree of cardiovascular impairment following SCI. During the acute phase of SCI, individuals typically present with neurogenic shock, a condition predominantly characterized by the simultaneous presence of bradycardia (HR of less than 60 beats per minute) and arterial hypotension (systolic BP below 90 mmHg and diastolic BP below 60 mmHg; Furlan & Fehlings, 2008; Krassioukov, 2009; Popa et al. 2010). Hypotension from neurogenic shock can be especially dangerous when it contributes to ischemia. In this case, there is not enough blood (and therefore oxygen) being delivered to the spinal cord or vital organs and tissues, and the affected cells become damaged or destroyed. Neurogenic shock can persist for weeks and is typically counteracted with established treatments for hypotension, bradycardia, and hypothermia (Mack, 2013). For more information on SNS disruption and resulting cardiovascular dysfunction, refer to the Cardiovascular Complications during the Acute Phase of Spinal Cord Injury chapter in SCIRE version 5.0.