By: Jiayin Sun

Spinal cord injury, whether acute or non-traumatic, evolves characteristically toward a set of cellular behaviours that amplify the damage beyond the area affected by the initial lesion. The early stages of secondary degeneration begin within minutes of the insult, causing tissue necrosis [1]. Damage can continue up to weeks after injury, during which time a glial scar is formed and Wallerian degeneration of truncated axons occurs. Many of the symptoms associated with spinal cord injury may be elicited by changes in neural circuit wiring and plasticity following degeneration.

Secondary damage leads to an increase in the range of motor and somatosensory deficits predicted by the original injury. Although the causes of secondary degeneration have not been conclusively identified, much of recent research in the field has been aimed at elucidating the cellular mechanisms by which it occurs in attempts to find suitable methods to treat or prevent its onset. The ability to control secondary damage would greatly reduce the impairments facing spinal cord injury patients and improve their quality of life.

  1. Causes of Secondary Cell Death
  2. Secondary Glial Death
  3. Secondary Neuronal Death
  4. Wallerian Degeneration

Causes of Secondary Cell Death Outside the Area of Injury

Cell necrosis – the disordered tumefaction and lysis of organelles and the cell membrane, coupled with moderate DNA condensation – occurs upon mechanical stress at the site of injury and is known as primary damage [2] [3]. The paresis resulting from spinal cord injury (SCI) is however more often associated with the secondary cell death that follows.

Necrotic rupture of the cell releases many endogenous toxins into the extracellular fluid (ECF), altering its composition. Large amounts of K+ ions, which are deleterious to cells, are released, as well as glutamate, which is a major cause of neuronal death through excitotoxic parthanatos. Glutamate, through an unknown mechanism, causes local ischemia [4]. Edema occurs, putting pressure on the spinal cord and causing local hemorrhage through disruption of blood vessels [5]. The blood-brain barrier breaks down at these sites, allowing potentially harmful substances to pass through [6] [7]. Additionally, the ischemic tissue becomes hypoxic; the lack of oxygen as the final electron acceptor in the electron transport chain causes mitochondrial dysfunction and generation of free radicals. Reactive oxygen and reactive nitrogen species (ROS and RNS, respectively) are produced, leading to lipid peroxidation and disruption of the phospholipid membrane, culminating in membrane lysis and necrosis.

Additionally, glutamate binding to neural cells causes calcium influx through NDMA receptors and through Ca2+/Na+ pumps after glutaminergic depolarization. Calcium is necessary for many destructive cascades in the cell, including cytoskeleton disassembly and caspase/calpain activation, an essential step in apoptotic cell death.

Secondary Glial Death


As novel mechanisms of programmed cell death are being discovered, traditional definitions of such terms as apoptosis are now becoming obsolete. For the sake of this article, “apoptosis” will be used generally in reference to cell death involving DNA fragmentation, pyknosis (nuclear condensation), and maintenance of the plasma membrane until phagocytosis, and can be identified by various tests such as TUNEL staining, phosphohistone H2AX, and DNA laddering (tests for DNA fragmentation) [8]. It requires energy in the form of ATP and the synthesis of specific proteins [9].

Dysmetabolic perturbation due to hypoxic/ischemic stress signals for the initiation of the apoptosis cascade. From there, a positive feedback loop is initiated, in which nucleolytic pyknosis is induced within 24 hours of the injury and leads to phosphorylation of the H2AX histone [10]. This signals for increased permeability of the mitochondrial membrane and the release of cytochrome c, which binds with apoptotic protease activating factor-1 (APAF-1) in the cytosol to form the apoptosome complex. Recruitment of procaspase-9 leads to activation of the effector caspase-3, which causes further DNA fragmentation [11].

It has been proposed that apoptosis occurs outside the initial area of injury due to the spread of calcium released by acute damage [12]. Calcium influx activates caspases and calpains, leading to cell membrane breakdown and further release of calcium [13]. However, it has also been proposed that the radius of calcium spreading cannot account for the extent of secondary damage and that other mechanisms must be involved [14].

Glial Cells are susceptible to Apoptosis, but not Excitotoxic Parthanatos

Secondary glial cell death in the central nervous system (CNS) following SCI occurs mainly by apoptosis [15]. In the ventrolateral white matter of neonatal rat spinal cord preparations, it has been found that DNA fragmentation, and subsequently pyknosis, occurs strongly within 4-8 hours of injection of a pathological medium (PM) mimicking extracellular conditions following acute SCI [16] [17]. It has further been shown that 60% of cells in which pyknosis is observed die within the next 24 hours by caspase-3 mediated apoptosis [18]. Additionally, glial cells near the affected area are TUNEL-positive (traditionally taken as an apoptosis marker) 4 hours to 14 days after injury, indicating that apoptosis of glial cells is an ongoing process that continues long after injury [19].

Glial cells have been shown to be non-susceptible to glutaminergic excitotoxic cell death due to their role in sequestering glutamate and rendering it into glutamine [20]. Glial cell death encourages further neuronal death by demyelination, exposing axons to damage and leading to apoptosis and necrosis.

Secondary Neuronal Death

Glutamate Excitotoxicity
Proposed cell death cascades for apoptosis (A) and parthanatos (B). Image from Kuzhandaivel et al., 2011. Click to enlarge.

Neurons and oligodendrocytes are especially susceptible to damage by glutamate excitotoxicity after the massive amounts of glutamate released after SCI due to their high density of NMDA receptors [21]. Especially in excitatory neurons, glutamate binding to their receptors AMPA and NMDA causes overstimulation, resulting in large influxes of calcium, ATP depletion, and ion imbalance, altering the integrity of the plasma membrane and activating cell proteases [22]. Motor neurons are especially vulnerable to excitotoxic cell death because they lack certain proteins that normally sequester the downstream effector calcium, such as calbindinin-D or parvalbumin [23].

Research into glutamate excitotoxicity uses kainate, a glutamate agonist that is not metabolized effectively and is impervious to glutamate transporters to create a sustained excitotoxic insult [24]. Pyknosis and TUNEL staining are highly observed in neurons 4-24 hours following kainate injection, but tests for apoptosis, such as H2AX histone phosphorylation and DNA laddering, are negative [25] [26]. This suggests that there is a different mechanism of programmed cell death (PCD) in these cells that is different from the apoptosis observed in glial cells.


A novel cell death pathway termed parthanatos has been proposed for the cell death observed in excitatory neurons following SCI. Parthanatos is distinguished from apoptosis by its reliance on the hyperactivity of the poly-A ribose polymerase-1 (PARP-1) enzyme, which catalyzes the conversion of damaged/fragmented DNA into poly-A ribose polymers (PAR) [27]. It has been shown that PAR binds to the mitochondrial membrane and is necessary for the release of apoptosis-inducing factor (AIF) from the mitochondrial membrane [28]. AIF subsequently translocates to the nucleus, where it acts to trigger pyknosis and DNA fragmentation; this has been determined as the commitment point for cell death in parthanatos [29] [30].

It was originally thought that the calpain I, a calcium activated enzyme responsible for the cleavage of many biological substrates, was necessary for the cleavage of the AIF and was additionally necessary for its release from the mitochondrial membrane. Wang et al.[31] have shown that although calpain I is able to cleave AIF in vitro, it is in fact the uncleaved form of the protein that translocates to the nucleus in parthanatos, indicating that calpain is not a necessary component of the parthanatos cell death mechanism.

Parthanatos is most highly observed in motor neurons and in dorsal horn neurons in the spinal cord, as these present the highest density of NMDA/kainate receptors [32]. It has been shown that PAR immunoreactivity is high in these neurons when undergoing cell death [33]. However, the full mechanism of parthanatos has not been elucidated, and further studies have found that PARP-1 inhibitors have little effect in preventing parthanatos, suggesting that parthanatos may in fact be PAR dependent as opposed to PARP-1 dependent, and that other mechanisms, such as PARP-2 activation, may be involved in the cell death cascade [34].

Wallerian Degeneration

Schematic of the progression of Wallerian degeneration after peripheral nerve damage. Image from Gaudet et al., 2011. Click to enlarge.

Wallerian degeneration is the process whereby the distal ends of truncated axons are degraded to make way for regeneration of nervous tissue. Degeneration of axons occurs within hours (rodents) to days (primates) of injury and is necessary for the progression of Wallerian degeneration [35] [36]. Calcium influx into the truncated axon activates calpains, leading to ubiquitin-proteosome complex dependent cytoskeleton degradation [37]. The affected axon ending swells into a bead and bursts, releasing its endogenous substances to the ECF.

Peripheral Nerve Injury – Schwann Cell Involvement

In the peripheral nervous system (PNS), Schwann cells are of primary importance in Wallerian degeneration. Degraded axons release ligands to the ECF that bind to toll-like receptors (TLRs) on myelinating Schwann cells, causing changes in gene expression [38]. Myelin production is halted and neurotrophic factors and immunological chemotaxic agents (ie. cytokines) are up-regulated [39]. Additionally, Schwann cells decrease their level of differentiation via an ubiquitin-proteosome complex and proliferate within their basal lamina to form bands of Bünger [40] [41]. These bands provide a source of neurotrophic substrates, such as laminin (an extracellular matrix (ECM) protein involved in cell adhesion) to encourage axon regeneration [42]. Knock-out studies of laminin have shown that it is an important contributor to nerve regrowth. Additionally, Schwann cells are able to limit neurotrophic factors when present in excess to prevent aberrant plasticity through binding to its p75NTR surface receptor [43].

Within the first 5 days of nerve injury, Schwann cells are the major phagocytotic agents of myelin debris, which contains compounds inhibitory to nerve regrowth [44] [45]. Phosphatidylcholine (PC), a membrane lipid, is broken down by phospholipase-A2 (PLA2) within the Schwann cell to yield lysophosphatidylcholine (induces myelin degradation) and arachidonic acid (supports immune inflammatory response) [46] . Schwann cells also produce tissue necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), amongst other chemotaxic agents [47]. These, combined with the compromised blood-brain barrier (mechanical and chemical stress), increase permeability of nervous tissue and allow recruitment of immune cells [48].

Denervated Schwann cells are only able to support nerve regeneration in the first 8 weeks of nerve damage, after which they atrophy or undergo apoptosis [49]. Schwann cell function as promoters of nerve regeneration can be rescued by treatment with tissue growth factor-β (TGF-β; autocrine from active Schwann cells; also from macrophages) [50].

*For a more detailed discussion of Schwann cell involvement in peripheral nerve injury, please visit Nerve Regeneration in the Peripheral Nervous System by Lydia Yeung.

Peripheral Nerve Injury – Immune Response

Immune cells are recruited by chemotaxic factors released by resident macrophages and Schwann cells as early as 8 hours after the initial injury [51]. Neutrophils are the first to be recruited; however, their turnover rate is high, and they undergo apoptosis soon after commencing phagocytosis of myelin debris. Resident macrophages also are heavily involved in myelin phagocytosis during early Wallerian degeneration [52]. Macrophages are further recruited preferentially to the vicinity of truncated axons by chemokines and cytokines such as TNF-α and galectin-1, a chemotaxic factor for monocytes (macrophage precursor) secreted by Schwann cells, peripheral neurons, and macrophages [53] [54]. Galectin-1 binding to macrophages is in turn chemotaxic for Schwann cells, setting a suitable environment for axon regrowth [55].

T lymphocytes are amongst the last immune cells to be recruited to the site of injury, with accumulation peaking between 14 – 28 days after injury [56]. Type 1 helper cells (Th1) secrete pro-inflammatory factors, while type 2 helper cells (Th2) secrete anti-inflammtory factors that suppress the immune inflammatory response activated by Th1. Regeneration of typical axons require the presence of both types of T cells [57].

*For a more detailed discussion of the immune response to SCI, please visit Pathophysiology of inflammation after SCI by Orest Kayder.

Central Nervous System Injury

Wallerian degeneration in the CNS is highly protracted in comparison to the PNS, accounting in part for the general inability to recover from SCI. Oligodendrocytes are much less supportive of recovery from injury than are Schwann cells – upon axon damage, they will typically undergo apoptosis or become quiescent [58]. Their inability for phagocytosis, as well as the formation of the glial scar, which reduces the permeability of the blood-brain barrier around the site of injury, result in decreased debris clearance and delayed progression of Wallerian degeneration [59] [60]. Additionally, oligodendrocytes do not offer much support of axonal regeneration through the secretion of neurotrophic factors [61].

Immune responses in the CNS show some toxicity as well to recovering neurons, further slowing Wallerian degeneration. Macrophages at the site of injury exhibit a pro-inflammatory phenotype (M1) during the early stages of Wallerian degeneration [62]. In the PNS, macrophages will switch to an anti-inflammatory M2 phenotype after a time, but the M1 phenotype persists indefinitely in the CNS. Both phenotypes promote neurite extension, but M1 is additionally neurotoxic through its associated inflammatory response.
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