Development of New Treatments for Neuropathic Pain Based on Imidazodiazepines

Mentor 1

Alexander Arnold

Start Date

29-4-2022 11:00 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. Patients often see minimal benefit but high addiction potential from these drugs. 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. These compounds have been used for decades to target and reduce neuronal firing that leads to pain. Additionally, tuning them to be anti-inflammatory presents a very promising, multi-faceted treatment option that could change the way chronic pain is managed. We have combined Greiss assay to quantify the amount of produced NO and a cytotoxicity assay that quantifies the amount of intracellular ATP to test compounds in a concentration dependent manner. At this point we were able to identify specific imidazodiazepines that showed significant reduction of NO without being cytotoxic. We have progressed to a serial dilution to quantify this reduction potential of target compounds at various concentrations.

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Apr 29th, 11:00 AM

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. Patients often see minimal benefit but high addiction potential from these drugs. 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. These compounds have been used for decades to target and reduce neuronal firing that leads to pain. Additionally, tuning them to be anti-inflammatory presents a very promising, multi-faceted treatment option that could change the way chronic pain is managed. We have combined Greiss assay to quantify the amount of produced NO and a cytotoxicity assay that quantifies the amount of intracellular ATP to test compounds in a concentration dependent manner. At this point we were able to identify specific imidazodiazepines that showed significant reduction of NO without being cytotoxic. We have progressed to a serial dilution to quantify this reduction potential of target compounds at various concentrations.