Uncovering a Healthier Remedy for Chronic Pain

Physicians and patients who are wary of addiction to pain medication and opioids may soon have a healthier and more natural alternative.

A Duke University study revealed that a derivative of DHA (docosahexaenoic acid), a main ingredient of over-the-counter fish oil supplements, can sooth and prevent neuropathic pain caused by injuries to the sensory system. The results appear online in the Annals of Neurology.

The research focused on a compound called neuroprotectin D1=protectin D1 (NPD1=PD1),  a bioactive lipid produced by cells in response to external stimuli. NPD1=PD1 is present in human white blood cells, and was first identified based on its ability to resolve abdominal and brain inflammation. 

"These compounds are derived from omega-3 fatty acids found in fish oil, but are 1,000 times more potent than their precursors in reducing inflammation," said Ru-Rong Ji, professor of anesthesiology and neurobiology at Duke University Medical Center and principal investigator of the study.  

The team used laboratory mouse models of nerve injuries to simulate pain symptoms commonly associated with post-surgical nerve trauma. They treated these animals with chemically synthesized NPD1=PD1, either through local administration or injection, to investigate whether the lipid compound could relieve these symptoms. 

Their findings revealed that NPD1=PD1 not only alleviated the pain, but also reduced nerve swelling following the injuries. Its analgesic effect stems from the compound’s ability to inhibit the production of cytokines and chemokines, which are small signaling molecules that attract inflammatory macrophages to the nerve cells. By preventing cytokine and chemokine production, the compound protected nerve cells from further damage. NPD1=PD1 also reduced neuron firing so the injured animals felt less pain.

Ji believes that the new discovery has clinical potential. “Chronic pain resulting from major medical procedures such as amputation, chest and breast surgery is a serious problem,” he said. Current treatment options for neuropathic pain include gabapentin and various opioids, which may lead to addiction and destruction of the sensory nerves. 

On the other hand, NPD1=PD1 can relieve neuropathic pain at very low doses and, more importantly, mice receiving the treatment did not show signs of physical dependence or enhanced tolerance toward the lipid compound. 

"We hope to test this compound in clinical trials," Ji said. The initial stages of the trial could involve  DHA administration through diet and injection. "DHA is very inexpensive, and can be converted to NPD1 by an aspirin-triggered pathway," he said. The ultimate goal is to develop a safer approach to managing chronic pain.

Researchers Investigate Mechanism of Alzheimer’s Therapy

Researchers at the University of Kentucky Sanders-Brown Center on Aging, led by faculty member Donna Wilcock, have recently published a new paper in the Journal of Neuroscience detailing an advance in treatment of Alzheimer’s disease.

Gammagard™ IVIg is a therapy that has been investigated for treatment of Alzheimer’s. Despite small clinical studies that have reported efficacy of the approach, the mechanism of action is poorly understood.

The UK researchers set out to investigate the mechanism by which the treatment may act in the brain to lower amyloid deposition (amyloid deposits being a key pathology in Alzheimer’s).

To conduct their investigation, researchers introduced IVIg directly into the brains of mice which carry a human gene causing them to develop amyloid plaques. They found that IVIg lowers amyloid deposits in the brains of the mice over the course of seven days. Their data suggest that the modulation of inflammation in the brain by IVIg is a key event that leads to the reduction in amyloid deposition.

The scientists hypothesize that the IVIg acts as an immune modulator, and this immune modulation is responsible for the reductions in amyloid pathology.

The data suggests that modulating the immune response in the brain may help ameliorate the Alzheimer’s pathology. Researchers are currently investigating other ways to produce the same modulation of the immune response because the access of IVIg to the brain when administered peripherally is very limited.

Promising Alzheimer’s ‘drug’ halts memory loss

A new class of experimental drug-like small molecules is showing great promise in targeting a brain enzyme to prevent early memory loss in Alzheimer’s disease, according to Northwestern Medicine® research.

Developed in the laboratory of D. Martin Watterson, the molecules halted memory loss and fixed damaged communication among brain cells in a mouse model of Alzheimer’s.

"This is the starting point for the development of a new class of drugs," said Watterson, lead author of a paper on the study and the John G. Searle Professor of Molecular Biology and Biochemistry at Northwestern University Feinberg School of Medicine. "It’s possible someday this class of drugs could be given early on to people to arrest certain aspects of Alzheimer’s."

Changes in the brain start to occur ten to 15 years before serious memory problems become apparent in Alzheimer’s.

"This class of drugs could be beneficial when the nerve cells are just beginning to become impaired," said Linda Van Eldik, a senior author of the paper and director of the University of Kentucky Sanders-Brown Center on Aging.

The study is a collaboration between Northwestern’s Feinberg School, Columbia University Medical Center and the University of Kentucky. It will be published June 26 in the journal PLOS ONE.

The novel drug-like molecule, called MW108, reduces the activity of an enzyme that is over-activated during Alzheimer’s and is considered a contributor to brain inflammation and impaired neuron function. Strong communication between neurons in the brain is an essential process for memory formation.

"I’m not aware of any other drug that has this effect on the central nervous system," Watterson said.

"These exciting results provide new hope for developing drugs against an important molecular target in the brain," said Roderick Corriveau, program director at the National Institute of Neurological Disorders and Stroke, which helped support the research. "They also provide a promising strategy for identifying small molecule drugs designed to treat Alzheimer’s disease and other neurological disorders."

Watterson and his collaborators have a new National Institutes of Health (NIH) award to further refine the compound so it is metabolically stable and safe for use in humans and develop it to the point of starting a phase 1 clinical trial.

(Image: Jay Vollmar)