The cause of lumbar disc herniation causing low back pain and sciatica is unknown. Spinal nerve root compression is not associated with clinical pain symptoms in all cases. Patients with herniated discs who have undergone chemical pulpotomy have experienced a reduction in sciatica pain, but CT scans show that mechanical compression is still present, suggesting that mechanical compression of the spinal nerve roots can cause injury but not necessarily pain. Numerous clinical studies have demonstrated that mechanical compression is not the only cause of nerve root pain and dysfunction.
Kuslish et al. suggested that the compressed nerve roots are sensitive to mechanical stimulation during epidural anesthesia or local anesthesia for removal of herniated discs, and animal studies by McCarron et al. and Olmarker et al. showed that the disc medullary nerve can cause inflammatory manifestations in the dura, nerve root cuff, and cauda equina. Although it is not possible to determine which component or chemical factor plays a major role in the inflammatory response after disc herniation, a large number of recent studies have shown that phospholipase A2 (PLA2) is very active in herniated disc tissue and that PLA2 purified from disc tissue has inflammatory properties. The role of PLA2 in the pathogenesis after disc herniation is reviewed. Han Jingqi, Department of Radiology, Huangdao District Hospital of Traditional Chinese Medicine, Qingdao, China
1. Molecular biology of PLA2
PLA2 (phospholipid-2-acyl hydrolase, EC3.1.1.4) is a lipolytic enzyme that specifically hydrolyzes the 2-position acyl site of glycosphingolipids to generate lysophospholipids and free fatty acids, mainly arachidonic acid, which is an important step in the inflammatory cascade response. Arachidonic acid is further converted into prostaglandins and other arachidonic acids such as thromboxane, leukotrienes, and platelet-activating factor, which are potent mediators of the inflammatory response.The biological roles of PLA2 are as follows.
①Production of inflammatory mediators through enzymatic digestion ;
②The enzymatic products of lysophospholipids and unsaturated free fatty acids can directly damage cell membranes and cause edema;
③The substrate of PLA2 is cell membrane phospholipids, so PLA2 can directly cause cell membrane damage;
④PLA2 can excite injury receptors and cause pain.
PLA2 has been found to be present in all cells. It is usually classified into two major types, namely extracellular PLA2 (low molecular weight: 14-18 kDa) and intracellular PLA2 (high molecular weight: 31-110 kDa). The extracellular PLA2 is also called non-pancreas-derived or secretory, and the intracellular PLA2 is called cytosolic. vadas et al. demonstrated that the secretion of PLA2 from lysosomes and intracellular granules into the intercellular space, intra-articular or vascular cavity can cause pathological processes in experimental and clinical inflammatory responses. vadas et al. injected human and cobra venom PLA2 1000-20 000 units/ml into the knee cavity of rats produced inflammatory changes. This activity corresponds to the level in the synovial fluid of rheumatoid arthritis. Histologically, the degree of acute and chronic joint inflammatory changes induced by both PLA2s was similar.
2. Elevated PLA2 activity in degenerated intervertebral discs
Saal et al. measured PLA2 activity in surgically resected herniated disc tissues of five patients and first found abnormally elevated PLA2 activity, indicating the presence of PLA2 chemical inflammatory mediators in disc tissues and suggesting that PLA2 in degenerated discs may play an initiating role in the inflammatory response. In humans, PLA2 is regulated by endogenous inhibitors and promoters such as PLA2-activating proteins, which can be activated once this balance is disturbed. Activation of PLA2 in the intervertebral disc may be associated with degeneration. There is a clear correlation between the pathophysiology of disc degeneration and lower back pain syndromes. Intervertebral disc degeneration involves altered biochemical homeostasis.
Kang et al. have successively reported that herniated cervical and lumbar disc tissue spontaneously produces more metalloproteinases (MMPs), nitric oxide (NO), interleukin-6 (IL-6) and prostaglandin E2 (PGE2) compared to normal discs, based on the biochemical effects of these chemokines in articular cartilage, leading to the speculation that they play a net loss of glycoproteins or other aspects of disc degeneration important roles.
For example, matrix lysis enzymes degrade the core proteins of proteoglycans, and NO, IL-6, and PGE2 play important roles in IL-1-induced inhibition of protein synthesis. Also, these chemokines are inflammatory mediators, and they may also play an important role in the pathophysiological pathogenesis of cervical and lumbar radiculopathy following disc herniation. Disorders of biochemical homeostasis of degenerated discs are the cause and consequence of structural defects in disc mechanics. The changing disc cellular synthesis capacity ultimately cannot balance the matrix breakdown caused by the activation of degradative enzymes within the disc, making it unable to adapt to the requirements of this physical change in the disc, resulting in changes in pH, aggregation, size, type, and charge density of glycoproteins, water content, and type and degree of cross-linking of collagen within the nucleus pulposus in this physicochemical environment.
PLA2 activity and quantity in degenerating discs are part of this altered balance. This potential impairment in the inhibition and regulation of inflammatory enzymes may play an important role in the initiation and maintenance of disc degeneration. PLA2 accumulates within the disc as a result of aging and degeneration, and each of the progressive biochemical changes described above, theoretically promotes the activation of PLA2 within the disc.
3. Mechanisms of PLA2 action in intervertebral disc disease
The presence of highly active PLA2 in herniated or degenerated disc tissue does not represent its role, nor does it prove that it can cause inflammation. To demonstrate the inflammatory properties of PLA2, Franson et al. injected PLA2 extracted from intervertebral disc tissue into the paws of mice, which caused a significant inflammatory response. This suggests that highly active PLA2 in intervertebral disc tissue is involved in the inflammatory response and that its elevated levels represent the involvement of chemical inflammatory mechanisms.
To demonstrate the damaging effect of PLA2 on nerves, Saal et al. injected highly purified human intervertebral disc PLA2 into the sciatic nerve of rats, along with snake venom PLA2 as a positive control group and saline injection as a negative control group. The results showed that animals in both human disc and snake venom PLA2 groups showed significant nerve damage responses, including nerve demyelination, lipid aggregation and axonal damage, while no nerve damage was seen in the saline injection group. This suggests that intervertebral disc PLA2 has neurotoxic effects.
PLA2 can cause chemical radiculitis by direct stimulation of nerve roots. In a related study, Ozaktay et al. applied PLA2 directly to nerve roots resulting in nerve excitation and neurological dysfunction.Cavanangh et al. have shown that exposure of the dorsal root ganglion and dorsal roots to the autogenous nucleus pulposus caused multi-unit discharges lasting several minutes.Chen et al. observed the effects of PLA2 on the structure and function of lumbar nerve roots.
They injected PLA2 into the lumbar epidural cavity of rats and saw localized demyelination of nerve root fibers after 3 d. At this time, mechanical stimulation of the nerve roots caused sustained ectopic discharge; after 21 d, myelin regeneration was seen and mechanical stimulation was given again, which caused only very brief ectopic discharges. They accordingly analyzed that sciatica after disc herniation is due to high concentrations of PLA2 injury to the nerve roots, causing the nerve to be in a hypersensitive state, and if mechanical pressure from the herniated disc is present at this time, it causes persistent pain in the sciatic nerve.
Injury to the nerve usually causes an increase in its excitability and causes ectopic impulses to be issued from the axons of primary afferent neurons, resulting in abnormal sensation and pain. Compression of the nerve trunk produces only transient impulses that do not cause pain but only transient sensory abnormalities, as is sometimes the case with inadvertent compression of the ulnar nerve at the elbow in daily life, as has been demonstrated by Howe et al. in a neurophysiological model in which normal nerve roots produce transient firing and inflamed damaged nerve roots produce sustained firing.
The mechanism of ectopic discharge production in the injured nerve may be related to the reorganization of macromolecules in the axonal membrane and the redistribution of sodium channels. Electrical generation in normal afferent nerves is dependent on adequate Na+ channel concentrations. After demyelination of nerve fibers, Na+ channels redistribute and accumulate to the demyelination site, causing the cell membrane there to be in a state of hypersensitivity to stimuli, sometimes even generating repetitive discharges spontaneously.
Kawakami et al. placed homogeneous disc myelin nuclei in the lumbar epidural cavity of rats to induce nociceptive hypersensitivity to mechanical stimuli in the animals. Normal disc tissue was negative for PLA2 immunoreactivity, but when placed in the lumbar epidural cavity for 1 and 2 weeks, PLA2 immunoreactivity increased. The study suggested that mechanical nociceptive hypersensitivity induced by the nucleus pulposus in the epidural cavity was a direct result of increased PLA2.
Later Kawakami et al. placed the same disc nucleus pulposus tissue on the sciatic nerve in rats, which also caused mechanical nociceptive hypersensitivity in rats. However, the application of the PLA2 inhibitor mepacrine resulted in normal sensation in the rats. This study suggests that PLA2 plays an important role in the pathogenesis of nerve root pain after disc herniation.
4. PLA2 antagonists for herniated discs
Kawakami et al. demonstrated that mepacrine can inhibit the mechanical nociceptive sensitization of the sciatic nerve by PLA2 in the intervertebral disc, but mepacrine has obvious gastrointestinal irritation and toxic effects on the central nervous system, making it difficult to be used in clinical practice. Other proven PLA2 inhibitors include adipine (quinacrine), manoalide, manoalogue and pbromophenacylbromine, but the inhibitory effects of these compounds on PLA2 not only lack specificity, but also have some toxic effects. Further studies on the mechanism of disc herniation and the development of effective PLA2 inhibitors with less toxic effects may be more beneficial for the treatment and recovery of patients with disc herniation.