A neuron

Science & Technology


The Science

Neuro Vigor Therapeutics and our collaborators are pioneering new drugs to inhibit toxic molecules called reactive aldehyde species (RAS), which have been implicated in the pathogenesis of multiple diseases, neuropathic pain and trauma.

RAS are a by-product of at least five biological pathways, (including lipid peroxidation, metabolism of polyamines and glucose, myeloperoxidase-induced breakdown of threonine, chemotherapies). Environmental sources of RAS include air pollution, auto exhaust, cigarette /e-cigarette smoking, fried foods, and alcoholic beverages.     

RAS covalently bind to cellular biomolecules such as proteins, causing misfolding, aggregation, and dysfunction. They also increase oxidative stress, incite inflammation, disrupt and damage mitochondria, alter and destroy DNA, deplete endogenous antioxidants, and stimulate pain. Acrolein is the most potent RAS and is responsible for >80% of RAS protein adducts. RAS exert damage via a vicious cycle in which they initiate damaging biochemical cascades and inflammation that in turn generate more RAS. Research demonstrates that RAS are significantly elevated in disease and trauma.

Reducing RAS has high therapeutic potential across a broad array of clinical applications. 

NVT solution

Dr Riyi Shi in Lab - Hydralazine

Our goal is to develop potential first-in-class, oral, blood-brain-barrier penetrant, disease-modifying, irreversible scavengers of RAS to treat diseases and conditions in which RAS play a central role.   

The company’s lead molecular scaffolds are based on discoveries of promising RAS scavenging compounds by the University of Western Australia, and are currently in preclinical development for our first medical indication: neuropathic pain in spinal cord injury (SCI).

Inhibiting the multiple sources of endogenous RAS is not a viable therapeutic strategy. As a result, NVT proprietary drugs will directly scavenge RAS, reducing the underlying pathological sources to achieve sustained health benefits and symptom improvement. The novel mechanism of action of NVT drugs is to attract and bind with toxic aldehydes before they bind with biomolecules such as proteins, DNA, pain receptors and myelin. In this way our drugs out-compete and deactivate RAS, protecting cells and tissue in the process.    

The company and our collaborators are currently pursuing this therapeutic strategy to address other sources of neuropathic pain (e.g., multiple sclerosis) and neurodegenerative diseases (multiple sclerosis and Parkinson’s Disease).     

Neuro Vigor Therapeutic's Clinical Focus Areas
Both preclinical and human data have linked RAS to the pathophysiology of numerous indications for which current treatments are inadequate.

Clinical Focus Areas

Spinal Cord Injury (SCI)

pathology of RAS in SCI

The initial SCI impact directly damages tissue. The lipid-rich environment of the spinal cord undergoes extensive lipid peroxidation, leading to massive oxidative stress and a spike in RAS, including acrolein, the most reactive RAS. Over several weeks these toxins increase and generate waves of secondary injury, leading to neuron damage and inflammation beyond the initial injury site.    

RAS, especially acrolein, are key factors in secondary injury. Highly toxic to spinal cord tissue, RAS increase pain and trigger a cascade of biochemical events that worsen the injury’s severity. As a known neurotoxin, acrolein has the ability to trigger neuropathic hypersensitivity by directly activating transient receptor potential ankyrin 1 (TRPA1), a sensory neuron channel widely implicated in pain signaling. As pro-inflammatory agents, RAS can stimulate the release of chemokines which likely further intensify pain through known mechanisms. Direct pre-clinical evidence demonstrates RAS and their actions on critical pain receptor TRPA1 produce/sustain Neuropathic Pain (NP) in SCI. Post-SCI excess RAs are:

  1. TRPA1 upregulators,
  2. direct TRPA1 activators,
  3. TRPA1 modulators that lower activation thresholds

Collectively, these post-SCI changes create pain neuraxis hyperexcitability.

Reducing RAS as a therapy for SCI NP

Man with SCI in wheelchair

Our team and collaborators aim to develop the first disease-modifying therapy for SCI-NP reduction. 

NVT therapies are not traditional analgesics; they reduce RAS, a critical cause of SCI NP.   As RAS proliferate during SCI progression, our proprietary drugs are designed to  bind with them, preemptively halting their damage to neurons and their activation of TRPA1. Robust pre-clinical research demonstrates that such RAS inhibition reduces NP by up to 50% and is also neuroprotective, preventing neural degeneration, hyperexcitability, and inflammation. RAS-reducing compounds are not direct neuromodulators and likely represent alternatives with fewer side effects compared to current SCI NP drugs.

We and our collaborators are engaged in drug development efforts to pinpoint new chemical entities (NCEs) with superior RAS-scavenging and pre-clinical efficacy in lowering SCI NP in animal models. Our novel direct-RA-scavenging drug family was selected for optimization due to their unique, first-in-class abilities to prevent cysteine-alkylation, the major protein modification by RAS. Cysteine binding is critical in SCI-NP, as it is the key mechanism underlying RA-induced effects on TRPA1 expression and hyperactivation. Our compounds reduce RAS more robustly than predecessors and, for the first time, effectively prevent cysteine residue binding by RAS. Our drugs also do not exhibit opioid activity at physiologically relevant doses.

Our team and collaborators aim to develop the first disease-modifying therapy for Spinal Cord Injury - Neuropathic Pain reduction. 

Neuropathic pain (NP)

Impact of RAS on NP

It is well established that inflammation and oxidative stress contribute to the initiation and maintenance of NP. 

Research has demonstrated that RAS generate and are in turn produced by these key contributors to NP, forming a vicious cycle. Our chief scientist has also found that RAS play a critical role in neuropathic pain-related behavior.   RAS are capable of activating the transient receptor potential ankyrin 1 (TRPA1) cation channel, known to be involved in the transmission and propagation of neuropathic pain. In addition, RAS are pro-inflammatory agents, stimulating the release of chemokines which likely further intensify pain through known mechanisms.

Role of TRPA1 in NP

Many studies have implicated critical pain receptor TRPA1 in pain signaling. Selective TRPA1 inhibition or genetic knockout relieves pain, reproduced in humans where selective TRPA1 activation causes pain and inhibition reduces pain. 

RAS have been shown to increase TRPA1 expression, leading to hypersensitization and therefore the development of NP. Following neurological trauma, RAS levels increase within 1 h and remain elevated in spinal cords, serum, and urine of rats for at least 2–4 weeks post-spinal cord injury (SCI). In lab (guinea pig, rat) and natural SCI (dog), tissue acrolein levels reach levels 5 – 25 times higher than levels observed in uninjured animals. RAS injection into uninjured spinal cords causes TRPA1 elevations and mimics SCI-NP behavioral hyperalgesia and neuronal hyperactivation. 

RAS lower pain neuron activation thresholds, hypersensitize them and increase their firing rates, and result in increased pain behaviors in numerous neuroinflammatory pain models. We and others have shown that RAS upregulates, directly activates and lowers activation levels of TRPA1.

These TRPA1-centered changes are one of many possible ways that RAS  contributes to neuroinflammatory pain.  We expect similar modifications and actions on other pain-relevant channels by RAS to be possible, though understudied presently. Collectively, these changes create pain neuraxis hyperexcitability leading to NP, and reduction of RAS improves pain-relevant outcomes in neuron physiology and animal behavior.

Scavenging RAS, reducing pain

NVT proprietary drugs will directly scavenge RAS, inhibiting the feedback loop and preventing further (or increasing) generation of RAS. NVT is developing novel, potent, oral, blood-brain-barrier penetrant, and disease-modifying scavengers of RAS to treat diseases and conditions in which RAS play a central role.

In pre-clinical models, reducing RAS levels via direct scavenging decreased the severity of pain-relevant behavior (mechanical, thermal, and chemical paw withdrawal thresholds), improved electrophysiology (reduced neuron firing rates), and restored tissue physiology (reduced RA-protein adducts, TRPA1 levels, inflammation). Other research groups have observed RAS-scavenging therapies’ ability to reduce central affective behavioral pain responses in animal models of neuroinflammatory pain. 

NVT drug discovery/ development efforts are focused on identifying and optimizing novel analogues of an FDA-approved drug that also directly scavenges RAS (but not as its stated MOA). As the structural basis for our drug’s development, this pathfinder drug will speed our pursuit of compounds that have the safety, efficacy and PK/ADME characteristics we seek. The pathfinder drug reduces neuro-inflammatory pain in relevant animal models (diabetic neuropathy, formalin paw injection, spinal nerve ligation, sciatic crush injury, chemotherapy-induced neurotoxicity, spinal cord injury, and multiple sclerosis [EAE]). 

Our current lead analogue NVT-C001 reduces RAS more robustly than the pathfinder and, for the first time, effectively prevents cysteine residue alkylation caused by RA. Cysteine alkylation is the key mechanism underlying RAS-induced effects on TRPA1 expression and hyperactivation. NVT-C001 reduces RAS-mediated cell death in vitro, with a 5+X increase in effective potency over the pathfinder drug. 

NVT-C001 does not exhibit opioid agonism at physiologically relevant doses.

Reducing NP after spinal cord injury is our lead indication, but we view RAS scavenging as a platform technology both within and beyond the NP space.    We are investigating NVT compounds’ efficacy for other types of NP, such as multiple sclerosis, diabetic neuropathy, chemotherapy-induced peripheral neuropathy, and radiculopathy or peripheral nerve injuries.

RAS are produced by and generate inflammation and oxidative stress, key contributors to the onset and severity of neuropathic pain.

Multiple Sclerosis (MS)

Multiple Sclerosis (MS)

RAS-induced demyelination

Normal, healthy nerve conduction (top)
Impaired nerve conduction after RAS-induced demyelination (bottom)

Recent evidence suggests oxidative stress and its toxic byproducts play a critical role in demyelinating and damaging axons in MS. To date, free radical reduction approaches to reduce oxidative stress have been ineffective at treating MS or preventing its progression.  

Our chief scientist, Dr. Riyi Shi, has developed compelling evidence to implicate reactive aldehydes (RAS), especially acrolein (the most plentiful and reactive RAS) in the pathophysiology of MS.We and our collaborators continue to strengthen the case for RAS as causal, addressable pathologic factors in MS progression and MS neuropathic pain. 

RAS are generated in the body by lipid peroxidation and other biological processes and are potent agents of inflammation and oxidative stress. In MS animal models, acrolein levels demonstrate sustained elevations, damaging to myelin and neurons while perpetuating oxidative stress and inflammation. In a study with the Indiana University School of Medicine, Dr. Shi also found MS patients had much higher acrolein levels than healthy adults. RAS scavengers mitigate myelin/nerve damage and reduce severity and progression of disease in MS animal models.   

Acrolein scavenging therapies in MS animal models (EAE) prevent demyelination and enable endogenous repair mechanisms to preserve neuronal function. Ultimately, as measured by motor function preservation, this slows disease progression and reduces its severity. 

Supported by a grant from the U.S. National MS Society, our two partners, Dr. John Chen and Purdue University, are investigating the correlation between acrolein and Myeloperoxidase (MPO), a frequently used biomarker of inflammation. They are also examining the effect of RAS scavenging on this correlation.    

We are developing a superior RAS-reducing drug with exciting potential to become a novel stand-alone or adjunctive MS therapy allowing:

  1. treatment earlier in the disease progression including RAS reduction as a means to delay onset for patients who demonstrate a genetic MS proclivity or RAS sensitivity;
  2. treatment to replace drugs which generate most severe patient side effects;
  3. treatment to synergistically augment existing therapies with co-administration;
  4. treatment capable of reducing the severity of relapses and frequency of attacks while promoting natural re-myelination;
  5. treatment which delays disease progression, e.g. from relapsing remitting to progressive.
We are developing a superior RAS-reducing drug with exciting potential to become a novel stand-alone or adjunctive MS therapy.



Man with Parkinsons

PD is a chronic, progressive nervous system disease leading primarily to a severe movement disorder.  The central pathology to PD is the progressive death of dopaminergic (DA) neurons in the substantia nigra (SN) that project into the striatum, a brain area critical for motor function.   Within brain cells, PD also generates clumps of cellular materials called Lewy bodies whose composition includes a widespread aggregated protein, alpha-synuclein (a-synuclein) that cells cannot process.    

Despite decades of research, the mechanisms of DA neuron destruction are largely unknown. Consequently, no established treatment is available to curtail the neuronal cell death and the pathological progression of PD, and the only available clinical therapeutic options are mainly for symptom relief.

While the exact cause of PD is unknown, oxidative stress has been considered as one of the most important contributors to SN cell death in PD.    Research shows that Reactive Aldehyde Species (RAS), of which acrolein is the most toxic, may play a key role in PD pathology.    Acrolein, as both a product of and catalyst for lipid peroxidation, is a key factor in perpetuating oxidative stress.    Clinical studies have reported significant acrolein levels in brain and spinal cord of patients with central nervous system (CNS) neurodegenerative diseases, including Parkinson’s (PD).

NVT’s chief scientist, Riyi Shi has demonstrated that acrolein is elevated in a rat model of PD (6-hydroxydopamine [6-OHDA]).   Injecting acrolein into a rat brain can reproduce PD-like symptoms and pathologies mirroring those seen in 6-OHDA injected rats.    And lowering acrolein using a known RAS scavenger such as hydralazine (HZ), or Dimercaprol (DP) mitigates PD pathologies, tissue damage and motor deficits.   Acrolein can also directly cause α-synuclein (α-syn) aggregation, a hallmark of PD pathology, in both cell-free systems and in vivo experiments.   Acrolein and other RAS may be a key therapeutic target and reducing RAS may represent a novel neuroprotective strategy for mitigating DA cell death.

Neuropathic pain (NP) is an important non-motor PD symptom, present in up to 85% of PD patients, and greatly impacts their quality of life.    Preclinical evidence points to acrolein as an important inducer of sensory hypersensitivity in 6-OHDA rats and in PD-related pain, likely through a TRPA1-related mechanism.   Dr. Shi observed that scavenging acrolein significantly reduced neuropathic pain-like behaviors in all three nociceptive modalities of 6-OHDA rats, suggesting that acrolein/RAS are likely involved in the sensory disturbances observed in this PD animal model.

The preclinical case is strong that RAS reduction has exciting potential to become a novel and feasible strategy to combat neurodegeneration and reduce NP in PD.    With the right collaboration, we hope to adapt our unique RAS-scavenging drug to help moderate disease progression and ease symptoms for PD patients.

The preclinical case is strong that RAS reduction has exciting potential to become a novel and feasible strategy to combat neurodegeneration and reduce NP in PD. 

Research Publications

Spinal Cord Injury (SCI)

Neuropathic Pain (NP)

Multiple Sclerosis (MS)


Other Indications