The title of their poster was “Mitochondrial electron transport chain (ETC) changes in spinal cord gray and white matter of ALS patients”.  This was a collaborative project between the CMMB Department and the USF Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair.  The project was supported by departmental funds for Dr. Patrick Bradshaw, Ph.D., and Dr. Svitlana Garbuzova-Davis, Ph.D., D.Sc.

Scientists at the University of South Florida’s Center of Excellence for Aging and Brain Repair and collaborators continue to advance our understanding of brain disease mechanisms and new therapeutic agents and strategies for treating these diseases.

A list of our recently published articles is appended below with links to the full texts.

1. Brown, L.A., Scarola, J., Smith, A. J., Sanberg, P.R., Tan, J., Giunta, B. The role of tau protein in HIV-associated neurocognitive disorders. Molecular Neurodegeneration 2014 Oct 10; 9(1):40. doi:10.1186/1750-1326-9-40. PMID: 25304757.

2. Smith, A. J., N. K. Duggirala, L. Wojtas, R. D. Shytle. and M. J. Zaworotko. Physical stability enhancement and pharmacokinetics of lithium ionic cocrystals with glucose. Crystal Growth & Design 2013 Oct 6; doi: 10.1021/cg501310d.

3. Acosta SA, Tajiri N, de la Pena I, Bastawrous M, Sanberg PR, Kaneko Y, Borlongan CV. Alpha-synuclein as a Pathological Link between Chronic Traumatic Brain Injury and Parkinson’s disease. J Cell Physiol. 2014 Sep 24. doi: 10.1002/jcp.24830. PMID: 25251017.

4. Tajiri N, Duncan K, Borlongan MC, Pabon M, Acosta S, de la Pena I, Hernadez-Ontiveros D, Lozano D, Aguirre D, Reyes S, Sanberg PR, Eve DJ, Borlongan CV, Kaneko Y. Adult stem cell transplantation: is gender a factor in stemness? Int J Mol Sci. 2014 Aug 28;15(9):15225-43. doi: 10.3390/ijms150915225. PMID: 25170809.

5. Li, S., Deng, J., Hou, H., Tian, J., Giunta, B., Wang, Y., Sawmiller, D., Smith, A. J., Sanberg, P. R., Obregon, D., Mori, T., Tan, J. Specific antibody biding to the APP_672-699 region shifts APP processing from alpha to beta cleavage. Cell Death and Disease 2014 Aug 14. doi: 10.1038/cddis.2014.336.  PMID: 25118934.

6. Tajiri N, Acosta S, Portillo-Gonzales GS, Aguirre D, Reyes S, Lozano D, Pabon M, Dela Peña I, Ji X, Yasuhara T, Date I, Solomita MA, Antonucci I, Stuppia L, Kaneko Y, Borlongan CV. Therapeutic outcomes of transplantation of amniotic fluid-derived stem cells in experimental ischemic stroke. Front Cell Neurosci. 2014 Aug 13;8:227. doi: 10.3389/fncel.2014.00227.  PubMed PMID: 25165432.

7. Li S, Ma C, Shao G, Esmail F, Hua Y, Jia L, Qin J, Ren C, Luo Y, Ding Y, Borlongan CV, Ji X. Safety and Feasibility of Remote Limb Ischemic Preconditioning in Patients with Unilateral Middle Cerebral Artery Stenosis and Healthy Volunteers. Cell Transplant. 2014 Jul 30. PMID: 25198862.

Congratulations to all contributing authors!

Dr. Cesar Borlongan

USF Center of Excellence for Aging and Brain Repair Director, Dr. Cesar Borlongan, has been re-elected as Vice President of the International Placenta Stem Cell Society (IPLASS) for a term of four years. Established in 2009 by a multi-national group of scientists, IPLASS is an international scientific organization open to scientists who are working in the field of placenta-derived stem cells.

To learn more about the IPLASS, please visit their website.

Dr. Cesar Borlongan

USF Center of Excellence for Aging and Brain Repair Director, Dr. Cesar Borlongan, will be traveling to Granada, Spain to chair the International Placenta Stem Cell Society (IPLASS) meeting. This meeting will take place September 10-12, 2014. Dr. Borlongan is currently serving as Vice President of IPLASS and will also be presenting some of his group’s current research, titled “Antiinflammatory effects of amnion-derived stem cell grafts in stroke and traumatic brain injury”.

For more information about the IPLASS meeting, please visit IPLASS.

Dr. Paula Bickford

“The chemicals in blueberries scavenge free radicals and make cells more resilient to stress, which means the body and brain will be more resistant to decline and disease,” said Bickford.  The article is on stands now in the September issue and a link to the article online is available below. 

Link: FamilyCircle Magazine

Center of Excellence for Aging and Brain Repair scientists have been awarded a United States patent for their pioneering discoveries related to the treatment of ALS with umbilical cord blood cells.  “This patent, titled “Treating Amyloid Lateral Sclerosis (ALS) with Isolated Aldehyde Dehydrogenase-Positive Umbilical Cord Blood Cells” is the culmination of many years of research conducted by our research group” said Associate Professor and Inventor, Dr. Svitlana Garbuzova-Davis, Ph.D.

Svitlana Garbuzova-Davis, PhD

They are hopeful that with proper funding to spearhead required clinical trials, this new technology may someday soon help treat ALS, whereas current US FDA-approved medications only extend life span by months.

Link to patent: http://www.google.com/patents/US8765119

Dr. Sandra Acosta and Dr. Md Shahaduzzaman, both from the USF Center of Excellence for Aging and Brain Repair (CABR), were equally contributing first authors with Dr. Tajiri. Dr. Cesar Borlongan (CABR) and Dr. Paula Bickford (CABR) served as corresponding authors. Other contributing authors from CABR include Dr.Hiroto Ishikawa, Dr. Kazutaka Shinozuka, Dr. Mibel Pabon, Diana Hernandez-Ontiveros, Christopher Metcalf, Meghan Staples, Travis Dailey, Julie Vasconcellos, Giorgio Franyuti, and Dr. Yuji Kaneko. Dr. Lisa Gould, Dr. Nikita Patel, and Dr. Denise Cooper, all of the James A. Haley Veterans Affairs Hospital and the USF Department of Molecular Medicine, were also contributing authors.

The Society for Neuroscience is the world’s largest organization of scientists and physicians devoted to understanding the brain and nervous system. The nonprofit organization, founded in 1969, now has nearly 42,000 members in more than 90 countries and 130 chapters worldwide. Its mission is to advance the understanding of the brain and the nervous system by bringing together scientists of diverse backgrounds, by facilitating the integration of research directed at all levels of biological organization, and by encouraging translational research and the application of new scientific knowledge to develop improved disease treatments and cures.

For a link to the article, click here.

A team of USF researchers led by Dr. Doug Shytle of USF Neurosurgery & Brain Repair and Dr. Mike Zaworotko of USF Chemistry have applied crystal engineering techniques to create novel ionic cocrystals of lithium. One of these cocrystals was subjected to a battery of efficacy and pharmacokinetic experiments compared to conventional lithium therapeutics.

Ionic cocrystal, LISPRO

Their study was published in Molecular Pharmaceutics and the full text is freely available here.

Their findings were recently reported online in the peer-reviewed journal PLoS ONE.

“The transplanted stem cells serve as migratory cues for the brain’s own neurogenic cells, guiding the exodus of these newly formed host cells from their neurogenic niche towards the injured brain tissue,” said principal investigator Cesar Borlongan, PhD, professor and director of the USF Center for Aging and Brain Repair.

Based in part on the data reported by the USF researchers in this preclinical study, the U.S. Food and Drug Administration recently approved a limited clinical trial to transplant SanBio Inc’s SB632 cells (an adult stem cell therapy) in patients with traumatic brain injury.

Stem cells are undifferentiated, or blank, cells with the potential to give rise to many different cell types that carry out different functions. While the stem cells in adult bone marrow or umbilical cord blood tend to develop into the cells that make up the organ system from which they originated, these multipotent stem cells can be manipulated to take on the characteristics of neural cells.

To date, there have been two widely-held views on how stem cells may work to provide potential treatments for brain damage caused by injury or neurodegenerative disorders. One school of thought is that stem cells implanted into the brain directly replace dead or dying cells. The other, more recent view is that transplanted stem cells secrete growth factors that indirectly rescue the injured tissue.

The USF study presents evidence for a third concept of stem-cell mediated brain repair.

The researchers randomly assigned rats with traumatic brain injury and confirmed neurological impairment to one of two groups. One group received transplants of bone marrow-derived stem cells (SB632 cells) into the region of the brain affected by traumatic injury. The other (control group) received a sham procedure in which solution alone was infused into the brain with no implantation of stem cells.

At one and three months post-TBI, the rats receiving stem cell transplants showed significantly better motor and neurological function and reduced brain tissue damage compared to rats receiving no stem cells. These robust improvements were observed even though survival of the transplanted cells was modest and diminished over time.

The researchers then conducted a series of experiments to examine the host brain tissue.

At three months post-traumatic brain injury, the brains of transplanted rats showed massive cell proliferation and differentiation of stem cells into neuron-like cells in the area of injury, the researchers found. This was accompanied by a solid stream of stem cells migrating from the brain’s uninjured subventricular zone — a region where many new stem cells are formed – to the brain’s site of injury.

In contrast, the rats receiving solution alone showed limited proliferation and neural-commitment of stem cells, with only scattered migration to the site of brain injury and virtually no expression of newly formed cells in the subventricular zone. Without the addition of transplanted stem cells, the brain’s self-repair process appeared insufficient to mount a defense against the cascade of traumatic brain injury-induced cell death.

The researchers conclude that the transplanted stem cells create a neurovascular matrix that bridges the long-distance gap between the region in the brain where host neural stem cells arise and the site of injury. This pathway, or “biobridge,” ferries the newly emerging host cells to the specific place in the brain in need of repair, helping promote functional recovery from traumatic brain injury.

Article citation:
“Stem Cell Recruitment of Newly Formed Host Cells via a Successful Seduction? Filling the Gap between Neurogenic Niche and Injured Brain Site;” Naoki Tajiri, Yuji Kaneko, Kazutaka Shinozuka, Hiroto Ishikawa, Ernest Yankee, Michael McGrogan, Casey Case, and Cesar V. Borlongan; PLOS ONE 8(9): e74857. Published Sept. 4, 2013.

Stroke is a leading cause of death and disability in the United States, and increases the risk for dementia.

“Approximately 80 percent of strokes are ischemic strokes, in which the blood supply to the brain is restricted, causing a shortage of oxygen,” said study lead author Svitlana Garbuzova-Davis, PhD, associate professor in the USF Department of Neurosurgery and Brain Repair. “Minutes after ischemic stroke, there are serious effects within the brain at both the molecular and cellular levels. One understudied aspect has been the effect of ischemic stroke on the competence of the blood-brain barrier and subsequent related events in remote brain areas.”

Using a rat model, researchers at USF Health investigated the subacute phase of ischemic stroke and found deficits in the microvascular integrity in the brain hemisphere opposite to where the initial stroke injury occured.

The study was published in the May 10, 2013 issue of PLOS One.

The USF team found that “diachisis,” a term used to describe certain brain deficits remote from primary insult, can occur during the subacute phase of ischemic stroke. The research discovered diachisis is closely related to a breakdown of the blood-brain barrier, which separates circulating blood from brain tissue.

In the subacute phase of an ischemic stroke, when the stroke-induced disturbances in the brain occur in remote brain microvessels, several areas of the brain are affected by a variety of injuries, including neuronal swelling and diminished myelin in brain structures. The researchers suggest that recognizing the significance of microvascular damage could make the blood-brain barrier (BBB) a therapeutic “target” for future neuroprotective strategies for stroke patients.

The mechanisms of BBB permeability at different phases of stroke are poorly understood. While there have been investigations of BBB integrity and processes in ischemic stroke, the researchers said, most examinations have been limited to the phase immediately after stroke, known as acute stroke. Their interest was in determining microvascular integrity in the brain hemisphere opposite to an initial stroke injury at the subacute phase.

Accordingly, this study using rats with surgically-simulated strokes was designed to investigate the effect of ischemic stroke on the BBB in the subacute phase, and the effects of a compromised BBB upon various brain regions, some distant from the stroke site.

“The aim of this study was to characterize subacute diachisis in rats modeled with ischemic stroke,” said co-author Cesar Borlongan, PhD, professor and vice chairman for research in the Department of Neurosurgery and Brain Repair and director of the USF Center for Aging and Brain Repair. “Our specific focus was on analyzing the condition of the BBB and the processes in the areas of the brain not directly affected by ischemia. BBB competence in subacute diachisis is uncertain and needed to be studied.”

Their findings suggest that damage to the BBB, and subsequent vascular leakage as the BBB becomes more permeable, plays a major role in subacute diachisis.

The increasing BBB permeability hours after the simulated stroke, and finding that the BBB “remained open” seven days post-stroke, were significant findings, said Dr. Garbuzova-Davis, who is also a researcher in USF Center for Aging and Brain Repair. “Since increased BBB permeability is often associated with brain swelling, BBB leakage may be a serious and life-threatening complication of ischemic stroke.”

Another significant aspect was the finding that autophagy — a mechanism involving cell degradation of unnecessary or dysfunctional cellular components –plays a role in the subacute phase of ischemia. Study results showed that accumulation of numerous autophagosomes within endothelial cells in microvessels of both initially damaged and non-injured brain areas might be closely associated with BBB damage. Autophagy is a complex but normal process usually aimed at “self-removing” damaged cell components to promote cell survival. It was unclear, however, whether the role of autophagy in subacute post-ischemia was promoting cell survival or cell death.

More than 30 percent of patients who survive strokes develop dementia within two years, the researchers noted.

“Although dementia is complex, vascular damage in post-stroke patients is a significant risk factor, depending on the severity, volume and site of the stroke,” said study co-author Dr. Paul Sanberg, USF senior vice president for research and innovation. “Ischemic stroke might initiate neurodegenerative dementia, particularly in the aging population.”

The researchers conclude that repair of the BBB following ischemic stroke could potentially prevent further degradation of surviving neurons.

“Recognizing that the BBB is a therapeutic target is important for developing neuroprotective strategies,” they said.

In addition to researchers from USF, researchers from the Ribeirao Preto School of Medicine, University of Sao Paulo, Sao Paulo, Brazil, contributed to the study.

The study was supported by the National Institutes of Health (1RO1NS071956-01A1) and the James and Esther King Biomedical Research Program (1KG01-33966).

The full study can be found here.