The Involvement of Caspases in Neuroinflammation and Neuronal Apoptosis in Chronic Pain and Potential Therapeutic Targets

Abstract

Chronic pain is a common, complex and unpleasant sensation following nerve injury, tissue trauma, inflammatory diseases, infection and cancer. It affects up to 25% of adults and is increasingly recognized as the leading cause of distress, disability and disease burden globally. Chronic pain is often refractory to most current analgesics, thus emphasizing the requirement for improved therapeutic medications. It is of great importance to elucidate the specific pathogenesis of chronic pain with different etiologies. Recent progress has advanced our understanding in the contribution of neuroinflammation and glial cells (microglia and astrocyte) activation in the plasticity of excitatory nociceptive synapses and the development of chronic pain phenotypes. Oxidative stress-associated neuronal apoptosis is also identified to be a pivotal step for central pain sensitization. The family of cysteine aspartate specific proteases (Caspases) has been well known to be key signaling molecules for inflammation and apoptosis in several neurological conditions. Recent studies have highlighted the unconventional and emerging role of caspases in microgliosis, astrocytes morphogenesis, chemokines release, cytokines secretion and neuronal apoptosis in initiating and maintaining synaptogenesis, synaptic strength and signal transduction in persistent pain hypersensitivity, suggesting the possibility of targeting caspases pathway for prevention and treatment of chronic pain. In this review, we will discuss and summarize the advances in the distinctive properties of caspases family in the pathophysiology of chronic pain, especially in neuropathic pain, inflammatory pain, cancer pain and musculoskeletal pain, with the aim to find the promising therapeutic candidates for the resolution of chronic pain to better manage patients undergoing chronic pain in clinics.

Cortexin® Ameliorates High Glucose-Induced Neuropathy in Cultured Rat Sensory Neurons

“…Reductions, being significant for 40 µg/mL, in high glucose-evoked neuropathy were obtained after Cortexin ® treatment. The finding that Cortexin ® prevents high glucose-mediated neuropathy in DRG neurons is supported by previous studies reporting neuroprotective actions of Cortexin ® [16] in diabetic polyneuropathy [10], inflammatory pain [12], and ischemic brain injury, which were regarded as rationale for this in vitro study. When Cortexin ® was applied in normoglycemic conditions.…”

“…In clinical setting, Cortexin ® has been shown to alleviate clinical symptoms of alcoholic and diabetic polyneuropathy [10]. Furthermore, Cortexin ® has been shown to exert neuroprotective effect by inhibition of the initiator caspase-8 [11], the mechanism has been shown to be involved in painful neuropathy [12]. It is plausible that Cortexin ® might prevent/treat diabetes-mediated sensory neuronal damage, improve peripheral neuropathy, and be useful for chronic neuropathic pain.…”

Lysophosphatidylcholine: Potential Target for the Treatment of Chronic Pain

“…Macrophages or microglia are activated in response to noxious stimuli such as nerve injury. Activated macrophages or microglia result in the production and release of pro-inflammatory mediators, which lead to the development of chronic pain [ 98 , 99 ]. LPC induced macrophage and microglia recruitment and activation in the mouse spinal cord [ 100 , 101 , 102 ].…”

The Role of Hydrogen Sulfide in Regulation of Cell Death following Neurotrauma and Related Neurodegenerative and Psychiatric Diseases

“…In addition, the heterogeneity of neurotrauma creates additional difficulties in their study and difficulties in developing and selecting a competent treatment strategy [ 3 ]. In addition, CNS and PNS injuries often lead to various mental disorders [ 4 , 5 , 6 , 7 , 8 ] and neurodegenerative diseases [ 9 , 10 , 11 , 12 , 13 ], which are accompanied by increased cell death of the nervous tissue [ 14 , 15 , 16 , 17 , 18 , 19 ]. It is worth noting that nerve cells are very sensitive to various influences, including microwave radiation, which can cause neurodegenerative diseases [ 20 ].…”