ARTICLE IN BRIEF
Investigators reported evidence that curcumin acts synergistically with stem cells in a mouse model of spinal cord injury, showing that the spice molecule has a biphasic action: in low doses it spurs stem cell proliferation while at higher doses it lowers inflammation.
SAN DIEGO—A small amount of curcumin, the curry ingredient that has been studied for several disorders as an anti-inflammatory, acted synergistically with stem cells to heal a spinal contusion induced in rats, according to early findings presented in November here at the meeting of the Society for Neuroscience.
The investigators — Meena Jhanwar-Uniyal, PhD, associate research professor of pathology and neurosurgery at New York Medical College; David Ormond, MD; and colleagues in the school's neurosurgery department — noted that a 2008 report in the Journal of Biological Chemistry had suggested a benefit in stem cell proliferation.
“Curcumin longo is an active compound found in turmeric spice that has been used for centuries as a topical or oral anti-inflammatory agent and transmitted through generations via folk stories in India,” said Dr. Jhanwar-Uniyal, an associate professor in the departments of experimental pathology and neurosurgery and director of the Neuro-Oncology and Molecular Genetics Laboratory. Indeed, curcumin has been studied as an anti-inflammatory in in vitro and animal models of cancer, Alzheimer disease, and Parkinson disease. But little had been done in spinal cord injury, she said.
The researchers used a model of spinal cord injury — a lab induced crush of surgically exposed spinal cord — to see if there was potential for more rapid healing. If stem cells isolated from the adult rat brain could repair the injury, the process might be aided by reducing the usual inflammation. Adding the curcumin molecule might help by reducing the usual glial scarring and swelling that can hinder repair of nerve damage, they reasoned.
The researchers used micropunches of the adult rat subventricular zone to obtain the stem cells. The subventricular zone was taken from coronal sections of forebrain. Cells expanded in vitro to form neurospheres — free floating clumps characteristic of cultures of neural progenitors — and were verified as such by finding the marker nestin, as well as other markers for embryonic stem cells.
The cells were then injected locally at the site of the contusion injury a week after the damage was induced.
Curcumin was tested at the low 0.5 mmol/kg dose or at a high dose of 60 mg/kg given by either epidural injection or IP injection. The investigators followed any recovery from the spinal cord injury by weekly observations of test scores for locomotor activity/hindlimb movement. Indeed, the induced injury healed more rapidly if the stem cells were accompanied by curcumin, in low doses, 500 mM. And the effect was beyond additive.
Dr. Ormond said: “We know there is at least a proliferative effect” of curcumin added to a culture of stem cells; in low curcumin doses, more of the cells form in culture, but at higher doses, it seems to lower inflammation.
The collaborators saw the best anti-inflammatory effect when curcumin was used alone at a high dose, 60 mg/kg; “then we gave a much lower dose of curcumin with stem cell transplantation and saw synergism,” better improvement than with either therapy alone, on the activity of the injured animals, Dr. Ormond noted.
He added that the 500 uM dose of curcumin “induces neural stem cell proliferation in vitro, and this may be one reason for the synergism in vivo.”
Aynun Begum, PhD, a postdoctoral fellow at the Western University Health Sciences in Pomona, CA, who was not part of the trial, commented that “curcumin has clear bioefficacy either in vitro or in an animal model, and also in humans. But this molecule has very poor availability in the brain and even also in blood.”
Dr. Begum, who conducts research on Alzheimer disease (AD), said that at her previous lab at the University of California-Los Angeles and VA Medical Center, had tried curcumin nanoparticles formulated with lipid and phosphotidyl choline as a brain delivery strategy in an AD mouse model; some of the findings were published in a 2008 report in the Journal of Pharmacology and Experimental Therapeutics.
“Curcumin with lipid or some other emulsifier can stabilize curcumin and can easily pass through gut to be available in blood, which ultimately can deliver it to the brain,” Dr. Begum said in an e-mail to Neurology Today.
Dr. Jhanwar-Uniyal said that curcumin is in phase 2 and 3 testing in various cancers, including colorectal and head and neck tumors. “We will be looking in detail on the molecular level as to what genes are being turned on or off,” Dr. Ormond said, “in the stem cells, and in the microenvironment of the injury.”
Begum AN, Jones MR, Frautschy SA, et al. Curcumin structure-function, bioavailability, and efficacy in models of neuroinflammation and Alzheimer's disease. J Pharmacol Exp Ther. 2008;326(1): 196-208. E-pub 2008 Apr 16.
Kim SJ, Son TG, Lee J, et al. Curcumin stimulates proliferation of embryonic neural progenitor cells and neurogenesis in the adult hippocampus. J Biol Chem
2008; 283(21): 14497-14505.