Betulinic acid, derived from the desert lavender Hyptis emoryi, attenuates paclitaxel-, HIV-, and nerve injury–associated peripheral sensory neuropathy via block of N- and T-type calcium channels

Abstract

The Federal Pain Research Strategy recommended development of nonopioid analgesics as a top priority in its strategic plan to address the significant public health crisis and individual burden of chronic pain faced by >100 million Americans. Motivated by this challenge, a natural product extracts library was screened and identified a plant extract that targets activity of voltage-gated calcium channels. This profile is of interest as a potential treatment for neuropathic pain. The active extract derived from the desert lavender plant native to southwestern United States, when subjected to bioassay-guided fractionation, afforded 3 compounds identified as pentacyclic triterpenoids, betulinic acid (BA), oleanolic acid, and ursolic acid. Betulinic acid inhibited depolarization-evoked calcium influx in dorsal root ganglion (DRG) neurons predominantly through targeting low-voltage-gated (Cav3 or T-type) and CaV2.2 (N-type) calcium channels. Voltage-clamp electrophysiology experiments revealed a reduction of Ca, but not Na, currents in sensory neurons after BA exposure. Betulinic acid inhibited spontaneous excitatory postsynaptic currents and depolarization-evoked release of calcitonin gene-related peptide from lumbar spinal cord slices. Notably, BA did not engage human mu, delta, or kappa opioid receptors. Intrathecal administration of BA reversed mechanical allodynia in rat models of chemotherapy-induced peripheral neuropathy and HIV-associated peripheral sensory neuropathy as well as a mouse model of partial sciatic nerve ligation without effects on locomotion. The broad-spectrum biological and medicinal properties reported, including anti-HIV and anticancer activities of BA and its derivatives, position this plant-derived small molecule natural product as a potential nonopioid therapy for management of chronic pain.

Betulinic Acid Inhibits ROS-Mediated Pyroptosis in Spinal Cord Injury by Augmenting Autophagy via the AMPK-mTOR-TFEB Signaling Pathway

“…Betulinic acid (BA), a natural pentacyclic triterpenoid, has gained considerable attention in recent years for its strong biological and medicinal properties [39]. Increasing evidence suggest that BA plays a substantial role in the treatment of various nervous system diseases such Alzheimer's disease [40] peripheral neuropathies [41]. Spinal cord injury is a devastating and common disease that in icts substantial physiological, emotional, and economic damage to patients, their families and societies worldwide.…”

Chemotherapy-induced peripheral neuropathy: part 1—current state of knowledge and perspectives for pharmacotherapy

“…Increased levels of Ca v channel mRNA within dorsal root ganglion neurons have been demonstrated in paclitaxeltreated mice, and Ca v channel antagonists (gabapentin and ethosuximide) effectively reduce hyperalgesia in rodents with paclitaxel-and vincristine-induced CIPN [17]. Many studies have confirmed a crucial role of N-type and T-type Ca v channels in paclitaxel-induced CIPN [74] as well as a key role of T-type Ca v channels in CIPN caused by vincristine [89].…”

“…Altered peripheral nerve excitability has also been implicated in CIPN development. The altered expression and functional impairment of voltage-gated sodium (Na v ), voltage-gated potassium (K v ), voltage-gated calcium (Ca v ) and transient receptor potential family (TRP) channels are regarded as the most prominent phenomena underlying CIPN caused by the platinum derivatives vincristine, paclitaxel and bortezomib [17,74].…”

KLHL1 Controls CaV3.2 Expression in DRG Neurons and Mechanical Sensitivity to Pain

“…T-type currents are up-regulated in various models of chronic pain, such as chronic constriction injury, spinal nerve ligation, STZ-diabetes, the carregin pain model, and drug-induced diabetic neuropathy (Jagodic et al, 2007(Jagodic et al, , 2008Melrose et al, 2007;Takahashi et al, 2010;Marger et al, 2011;Watanabe et al, 2015;Li et al, 2017;Bellampalli et al, 2019). Ca V 3.2 can be upregulated by increased expression of USP5, which interacts with and de-ubiquitinates these channels thereby decreasing their degradation (Garcia-Caballero et al, 2014;Stemkowski et al, 2016).…”