Development of new treatments for neuropathic pain based on imidazodiazepines
Mentor 1
Alexander Arnold
Start Date
1-5-2020 12:00 AM
Description
Currently, 7% of the US population has been diagnosed with neuropathic pain (NP). NP is mediated by inflammation of the associated peripheral sensory endings and is commonly associated with diabetic neuropathy, HIV infection, post-herpetic neuralgia and chemotherapy treatment for cancer. Opioids are currently one of the leading NP therapeutic choices, but their use is controversial. Additional treatments include tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors and anti-epileptics, which are often followed by second-line opioids and topical drugs or third-line strong opioids. Patients often see minimal benefit but high addiction potential from these drugs. Less than one-fourth of patients have experienced significant pain relief with these treatment options. Neuroinflammation is facilitated by activated microglia, the resident CNS macrophages. They have been implicated in many neuro-inflammatory diseases such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis as well as neuropathic pain. Novel imidazodiazepines have been identified that reduce NO production of microglia, a key inflammatory modulator that causes extensive cell damage. Current compounds of interest to decrease painful neuropathic stimuli are GL-IV-03 and MP-IV-010. We have applied a combined Greiss assay to quantify the amount of produced NO and a cytotoxicity assay that quantifies the amount of intracellular APT to test hit compounds in a concentration dependent manner. Furthermore, we have used antagonists of several pathways that include gamma amino butyric acid A receptors, opioid receptors, the peripheral benzodiazepine receptor and sigma receptors to further evaluate the mode of action of the lead compounds. The application of a murine formalin pain model showed significant analgesic effects of these compounds in vivo.
Development of new treatments for neuropathic pain based on imidazodiazepines
Currently, 7% of the US population has been diagnosed with neuropathic pain (NP). NP is mediated by inflammation of the associated peripheral sensory endings and is commonly associated with diabetic neuropathy, HIV infection, post-herpetic neuralgia and chemotherapy treatment for cancer. Opioids are currently one of the leading NP therapeutic choices, but their use is controversial. Additional treatments include tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors and anti-epileptics, which are often followed by second-line opioids and topical drugs or third-line strong opioids. Patients often see minimal benefit but high addiction potential from these drugs. Less than one-fourth of patients have experienced significant pain relief with these treatment options. Neuroinflammation is facilitated by activated microglia, the resident CNS macrophages. They have been implicated in many neuro-inflammatory diseases such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis as well as neuropathic pain. Novel imidazodiazepines have been identified that reduce NO production of microglia, a key inflammatory modulator that causes extensive cell damage. Current compounds of interest to decrease painful neuropathic stimuli are GL-IV-03 and MP-IV-010. We have applied a combined Greiss assay to quantify the amount of produced NO and a cytotoxicity assay that quantifies the amount of intracellular APT to test hit compounds in a concentration dependent manner. Furthermore, we have used antagonists of several pathways that include gamma amino butyric acid A receptors, opioid receptors, the peripheral benzodiazepine receptor and sigma receptors to further evaluate the mode of action of the lead compounds. The application of a murine formalin pain model showed significant analgesic effects of these compounds in vivo.
