Dehydrocorydaline can be a suitable candidate for analgesic purposes: a review on the current preclinical evidence

Abstract

Pain stands as one of the main factors related to human disability and suffering, with different classifications (e.g. acute/chronic, somatic/visceral, and malignant/non-malignant). The management of this factor is of great importance during the lifespan; however, the current suggested medications have not yet reflected sufficient effectiveness with minimum side effects. Therefore, applying an ideal strategy against conditions accompanied by pain is urgent. A growing body of evidence has recently highlighted that alkaloids as bioactive compounds with analgesic capacity can be effective in these conditions. Regarding this matter, dehydrocorydaline, a bioactive alkaloid derived from the tubers of Rhizoma Corydalis, has shown promising results in pain management in diseases, including Chronic constriction injury, bone cancer, sleep deprivation, and inflammatory pain. Also, dehydrocorydaline has been shown to exert different biological and pharmacological benefits, like anti-tumor, anti-inflammatory, anti-microbial, anti-viral, anti-nociceptive, and cardioprotective. Hence, in this literature review, we aimed to explore the potential of this alkaloid agent in these conditions with a mechanistic insight.

Introduction

Pain is known as one of the key contributors to human disability and suffering, with a worldwide prevalence estimated at 27.5%. It is also one of the most common causes of looking for medical care globally. ¹ The International Association for the Study of Pain (IASP) defines pain as an undesirable emotional and sensory experience related to actual or potential tissue damage. ² Physiologically, the ultimate purpose of pain is to warn the human body of detrimental situations posed by the internal or external environment. ³ Pain is commonly assigned into acute pain and chronic pain, with a duration of approximately 3 months serving as a tentative descriptive point in humans.^4,5 Acute pain exerts a protective role against potential health problems and is typically easy to manage. ⁶ Chronic pain can be harassing and is notoriously difficult to control. Its reasons can be various, encompassing musculoskeletal strain, metabolic or inflammatory diseases of the peripheral tissue, central or peripheral nervous lesion, and so on. ⁷ - Pain instigates an integrated response from the pain-related systems. This reaction to pain happens more sophisticatedly at the cortex levels in which pain is perceivable consciously, like the thalamus, anterior cingulate cortex, insular cortex, secondary somatosensory cortex, primary motor cortex, primary somatosensory cortex, and supplementary motor cortex. ⁸ The emotional response to pain is at a subconscious level, which is associated with the limbic system. In this system, pain experiences acquire a personal importance based on life experiences and an individual’s emotions. Fear and memory, which are monitored by structures such as the hippocampus, amygdala, and various subcortical areas, including the basal ganglia, possess a central role in pain emotional regulation.^9,10

Pain management is one of the vital aspects of life care throughout the human life span. ¹¹ However, the present pharmacological treatments for pain, especially chronic pain, not only have not addressed expected effectiveness yet but also pose serious risks for user patients.^12–14 Reports have pointed out that in 64% of subjects using administered painkillers, pain palliation is insufficient, and 14% of chronic pain patients do not continue these medications due to adverse effects. ¹⁵ Ergo, there is an unmet need to design or develop new types of analgesics and investigate their functionality for administration. ¹

These days, the analgesic potential of bioactive compounds, especially alkaloids, has been in the spotlight of scientists. Among these, the analgesic capacity of dehydrocorydaline, a bioactive alkaloid compound originating from the tubers of Rhizoma Corydalis, has been highlighted in some documents.^16–18 This alkaloid agent was first demonstrated to decrease the secretion of noradrenaline, which has a key role in pain transmission and perception from adrenergic nerve terminals. ¹⁶ Dehydrocorydaline, with the chemical formula C₂₂ H₂₄ NO₄ (Figure 1), possesses diverse pharmacological and biological benefits, including anti-tumor, anti-inflammatory, anti-microbial, anti-viral, anti-nociceptive, and cardioprotective for diverse cardiovascular diseases (e.g. atherosclerosis and myocardial ischemia-reperfusion injury).^19–22 Hence, the current narrative review aims to summarize and discuss evidence regarding the analgesic effects of this natural bioactive with a mechanistic insight to pave the way for scientists and clinicians to make a better decision on the application of dehydrocorydaline in clinical practice.

Figure 1.

Chemical structure of dehydrocorydaline.

Pain and classifications

As mentioned above, several categories have been determined for pain according to the pathophysiological mechanism, physical origin, duration, etiology, and anatomical locations.^23–25 Pain, according to the pathophysiological mechanism, is classified into nociceptive and neuropathic. Nociceptive pain happens when nociceptors are triggered by harmful stimuli, while neuropathic pain stems from damage or a failure within the nervous system. Although these kinds of pain can coexist, acute post-surgical pain is generally categorized as nociceptive.^26,27 Taking the physical origin into account, pain is grouped into somatic and visceral pain. Somatic pain results from external body structures comprising the bones, joints, muscles, ligaments, and skin. On the contrary, visceral pain originates from internal organs in pelvic, abdominal, and thoracic cavities. ²⁸ Having considered pain duration, it is categorized into acute, chronic, recurrent or episodic, Breakthrough, and end of dose pain. ²⁵ In the acute phase, pain has been recently initiated and probably is temporary, predominantly related to a specific illness or injury. The shift from acute to chronic phase usually takes approximately 12 weeks or once the pain is not directly related to the original injury. The chronic pain mainly continues following the injury improvement and may be unrelated to an evident underlying cause. ²⁹ In recurrent or episodic type, pain is experienced intermittently during a long period, and it can be insensible between episodes. ³⁰ Breakthrough pain means pain exacerbation, for instance, variations in chronic pain severity. ³¹ At the end of dose type, pain is sensible once medication levels drop to sub-therapeutic levels in the blood. ³² According to the etiology, pain is categorized into malignant or non-malignant pain. In the malignant one, pain is accompanied by cancer. Pain can be due to cancer itself or associated therapeutic strategies (e.g. surgery, radiotherapy, and chemotherapy). Also, non-malignant pertains to pain with no associations with malignancies.^33,34 Based on the anatomical locations, pain can also be classifiable, such as back, neck, or head pain. ³⁵

Dehydrocorydaline and pharmacological features

Several pharmacological and biological advantages have been mentioned for dehydrocorydaline, comprising anti-tumor, anti-inflammatory, anti-microbial, anti-viral, anti-nociceptive, and cardioprotective for diverse cardiovascular diseases (e.g. atherosclerosis and myocardial ischemia-reperfusion injury).^19–22 Pharmacokinetically, the bioavailability, stability, metabolism, and excretion of dehydrocorydaline are still being studied. The current evidence has shown that the oral administration of dehydrocorydaline has a suitable absorption; however, it is present in low concentrations within the systemic circulation. ³⁶ This is attributable to a potentially remarkable “first-pass” influence in the liver following oral administration. Therefore, information on the total excretion of alkaloids in the bile after oral consumption would be important for understanding the extent of absorption. ³⁶ Recently, it has been revealed that nitroreductase present in gut microbiota serves a key role in the metabolism of dehydrocorydaline by its conversion into a hydrogenated metabolite. The hydrogenated metabolite is more absorbable and has higher membrane permeability than dehydrocorydaline. This phenomenon answers the question of why dehydrocorydaline can have therapeutic effects on some diseases like coronary heart disease, despite having poor oral absorption. ³⁷ The cumulative excretion in urine and bile following a single intragastric dose of dehydrocorydaline (97.5 mg/kg) in male Sprague-Dawley rats was examined. The outcomes indicated that dehydrocorydaline is chiefly excreted in the bile after dehydrocorydaline administration orally. ³⁶ Regarding the possible toxicity of dehydrocorydaline, there are still insufficient documents. However, it is stated that it displays low acute toxicity, with an LD50 of approximately 277.5 ± 19.0 mg/kg in mice once taken orally, and 21.1 ± 1.4 mg/kg when administered intraperitoneally. ¹⁹

Dehydrocorydaline and analgesic effects

Some evidence has repotted promising outcomes regarding the analgesic effects of dehydrocorydaline in different animal models, including bone cancer, chronic constriction injury (CCI), sleep deprivation, and inflammatory pain models (Figure 2).

Figure 2.

A schematic representation about the analgesic effects of dehydrocorydaline on sleep deprivation, inflammatory pain, chronic construction injury, and bone cancer.

Bone cancer

It was found that during the progression of pain, reduced expression of IL-10, an anti-inflammatory cytokine, and elevated levels of IL-1β, a pro-inflammatory cytokine, are observed in the spinal cord of mice with bone cancer. In contrast, the research of Huo et al. implicated that dehydrocorydaline (10 mg/kg, IP) dramatically alleviated pain on day 14 following osteosarcoma establishment in mice. This result was along with M1 phenotype inhibition and the M2 phenotype promotion of microglia present in the spinal cord, as well as a decrease in inflammatory reactions. ¹⁸ The activation of microglia, as the main immune agent in the spinal cord, has a critical role in pathological events, assisting in incidence and sustaining bone cancer pain. ³⁸ The activated microglia include different cell populations with distinct and occasionally contradicting activities, where M1 and M2 phenotypes characterize the two opposing extremes of microglial polarization. ³⁹ The current reports have indicated dichotomous functional states of microglial polarization in the spinal cord associated with neuropathic pain conferred by nerve injury.^40–42 On the one hand, M1 microglia discharge pro-inflammatory mediators, comprising IL-1b and inducible nitric oxide synthase (iNOS), which are accompanied by the appearance of pathological pain. ⁴³ On the other hand, M2 microglia are related to the overexpression of anti-inflammatory factors, like arginase-1 (Arg-1), therefore attenuating neuropathic pain. ⁴⁴ Collectively, these reports indicated that dehydrocorydaline is able to relieve bone cancer pain by enhancing a shift in microglial polarization toward the M2 phenotype in the spinal cord. ¹⁸

Chronic constriction injury

Recently, the pain-reducing effects of dehydrocorydaline on neuropathic pain conferred by chronic constriction injury (CCI) have been highlighted in vivo by Hou and co-workers. In this research, A CCI was modeled in mice to confer neuropathic pain through ligation of the right common sciatic nerve. On the 14th day following CCI surgery, mice received dehydrocorydaline at a dose of 50 mg/kg intrathecally into the space between the fifth and sixth lumbar vertebrae (L5–L6). Pregnant ICR mice were ethically killed on embryonic day 14 to collect primary spinal neurons for in vitro assessments. Pain evaluation was done using the paw withdrawal mechanical threshold (PWMT) measurement. Immunofluorescence was utilized to detect microglia and astrocyte activation in the spinal cord. Also, the Western blot was used to examine expression levels of TNF-α, iNOS, IL-6, NR2B, and p-NR2B in primary neurons and the spinal cord. The attained findings revealed a remarked PWMT reduction, glial cell activation, and elevated levels of IL-6, TNF-α, iNOS, and a higher ratio of p-NR2B/NR2B in the spinal cord, all of which were reversed by injecting dehydrocorydaline intrathecally. Moreover, the ratio of p-NR2B/NR2B was decreased in p-NR2B/NR2B. These reports emphasize that dehydrocorydaline alleviates CCI-caused neuropathic pain by repressing neuron hyperactivity and neuroinflammation. ¹⁷

Sleep deprivation

Poor sleep is strongly linked with decreased volume of the gray matter in the anterior cingulate cortex, the medial precuneus cortex, and the hippocampus, making adolescents more vulnerable to pain exacerbation. ⁴⁵ In a recent study, the influences of sleep deprivation preoperatively on postoperative pain in adult mice and the therapeutic effectiveness of dehydrocorydaline obtained from Rhizoma Corydalis were explored. Preoperative SD notably reduced the paw withdrawal mechanical threshold (PWMT) value, signifying elevated pain sensitivity, and extended the duration of postoperative pain in adult mice. This phenomenon was associated with elevated microglial activation and neuroinflammation in the spinal cord, as evidenced by the triggered P2Y12/p38MAPK/NF-κB signaling pathway. ⁴⁶ The P2Y12 receptor, detected especially on microglia, has a vital function in mediating microglial activation and activating the p38MAPK-NF-κB signaling axis downstream, leading to the discharge of pro-inflammatory cytokines. ⁴⁷ On the other hand, IP administration of dehydrocorydaline repressed the P2Y12/p38MAPK/NF-κB signaling pathway, decreased microglial activation, and enhanced a shift from the M1 to the M2 phenotype. These occurrences resulted in a decrease in the expression levels of pro-inflammatory and amelioration of postoperative pain. ⁴⁶

Although the central nervous system (CNS) penetration of dehydrocorydaline appears limited, as described by Fujii et al. (1984), emerging evidence shows that this compound can modulate CNS neurotransmitter systems. ⁴⁸ Jin et al. (2019) reported that dehydrocorydaline increases central monoaminergic neurotransmitter concentrations in vivo, which may underlie some of its analgesic and neuromodulatory properties. ⁴⁹ Additionally, acetylcholinesterase inhibition by dehydrocorydaline was revealed in bioassays by Xiao et al. (2011) and Wang et al. (2018), suggesting a possible effect on cholinergic neurotransmission that could be relevant for pain modulation. ⁵⁰

Pharmacodynamically, Xu et al. (2021) provided compelling evidence that dehydrocorydaline exerts analgesic activity by inhibiting sodium channel Nav1.7 peak currents. Specifically, it promotes both the activation and inactivation phases of Nav1.7, a voltage-gated sodium channel critically involved in nociceptive signaling. This novel mechanism highlights the direct neuronal modulatory role of dehydrocorydaline in pain alleviation. ⁵¹

Inflammatory pain

Yin et al. have focused on the antinociceptive influences and the probable action mechanisms of dehydrocorydaline in two inflammatory pain models established in mice using formalin paw and acetic acid-induced writhing tests. The intraperitoneal (IP) injection of this alkaloid (3.6, 6, and 10 mg/kg) remarkably alleviated the formalin-induced pain responses caused by formalin in animals. This administration also addressed the antinociceptive potential of the acetic acid-caused writhing test dose-dependently. The pain-relieving influence of dehydrocorydalmine did not influence the motor responses and locomotor function, and no significant signs of toxicity (acute or chronic) were observed in the mice. The role of the opioid receptor in the central antinociceptive impacts was approved by IP injection of naloxone hydrochloride (2 mg/kg) as a non-selective blocker of opioid receptors. Other results showed that dehydrocorydaline decreases formalin-conferred paw edema, showing its possible action in attenuating inflammatory responses in the periphery. Further data divulged that this bioactive alkaloid lowered the expression levels of pro-inflammatory cytokines (e.g. IL-6, IL-1β, and TNF-α), as well as caspase 6 (CASP6), as an apoptotic marker in the spinal cord. ¹⁹ It is well-known that IL-6, IL-1β, and TNF-α released by glial cells in the spinal cord have imperative roles in key in establishing and sustaining inflammatory pain sensitization.^52,53 Also, the high levels of CASP6, an intracellular cysteine protease, can trigger TNF-α section mediated with microglia and adjust inflammatory pain and synaptic plasticity. ⁵⁴ For instance, Kong et al. (2020) demonstrated its notable anti-inflammatory properties. ⁵⁵ Ishiguro et al. (2011) found that dehydrocorydaline prevented the increases of pro-inflammatory cytokines IL-1β and IL-6 in the culture medium of lipopolysaccharide (LPS)-stimulated macrophages, indicating an immunomodulatory effect. ⁵⁶ Moreover, an older study by Kubo et al. (1994) showed that dehydrocorydaline significantly reduced paw edema induced by compound 48/80 or carrageenan in rat models, further supporting its peripheral anti-inflammatory action. ⁵⁷

Conclusion

Pain, a renowned contributor to human suffering and disability, remains one of the most common causative factors for looking for medical care. Pain, while protective in acute situations, confers significant challenges in the chronic phase on account of its complex causes and resistance to standard therapies. The current pharmacological strategies have failed to provide enough relief because many patients still experience adverse effects or unsatisfactory pain management. Dehydrocorydaline, an alkaloid with diverse pharmacological capacities (e.g. anti-inflammatory, anti-cancer, and anti-oxidative effects), has shown its meritoriousness as a suitable candidate for alleviating pain in various pain-related diseases, such as chronic constriction injury, bone cancer, sleep deprivation, and inflammatory pain, in preclinical studies. Dehydrocorydaline can act as an analgesic against the mentioned diseases through different mechanisms, such as regulation of neuroinflammation, microglial polarization, and suppression of the release of pro-inflammatory cytokines, accentuating its ability to address the emotional and sensory dimensions of pain. However, further research is important to completely comprehend the pharmacokinetics, bioavailability, and safety of this bioactive agent. Although primary outcomes are hopeful, translating these findings into clinical settings demands comprehensive investigation, including human trials, to approve its therapeutic capacity and optimize dosing approaches. Therefore, by linking conventional medicine with modern pharmacology, dehydrocorydaline can give rise to effective, innovative, and safer pain management, eventually promoting the quality of life for people experiencing chronic pain.