Neuroinflammation: Molecular Principles and Translational Approach August 23 - 30, 2014 Coordinator: Nicolas G. Bazan

Neuroinflammation: Molecular Principles and Translational Approach

August 23 - 30, 2014

Coordinator: Nicolas G. Bazan

LSU Center for Excellence in Neuroscience, New Orleans, USA

Faculty:

Scott Brady, University of Illinois, Chicago (USA)
David Brody, Washington University School of Medicine, St Louis (USA)
Marianne Schultzberg, Karolinska Institute, Stockholm (Sweden)
Thomas Moeller, Lundbeck Research, Paramus, USA
Michael T. Heneka, University of Bonn (Germany)
Haydee Bazan, LSU Center for Excellence in Neuroscience, New Orleans (USA)

The central nervous system is often referred to as an immunologically privileged site. While the blood–brain barrier (BBB) protects the central nervous system (CNS) from peripheral immune and inflammatory activation, the CNS is also able to induce the protective innate immune system in response to injury, including trauma, infection, stroke and neurotoxins. This acute inflammatory response is short-lived and generally beneficial in neutralizing potential threats to the CNS by minimizing cellular damage. On the other hand, a sustained chronic neuroinflammatory response can be detrimental and initiate neuronal damage, neuronal circuits impairments, astrocytic and microglia involvement and neurodegeneration via long-lasting formation and accumulation of neurotoxic proinflammatory mediators. New knowledge has revealed that macrophage lineage resident cells, microglia, perivascular macrophages and the other macrophage populations are engaged in homeostatic functions in the developing and adult nervous system. A critical reappraisal of their function is currently in progress in order to ascribe to these cells their full significance in pathophysiology of several neurological disorders and to understand how comorbid systemic disease and associated immune response impacts the nervous system and its inflammatory response.

The CNS's innate immune response involves intricate signaling circuitry and cellular networks. What was once considered an immune-privileged site is now recognized as having the ability to synthesize and release reactive molecules and pro-inflammatory mediators, as well as a capacity to respond to injury with anti-inflammatory, pro- homeostatic mechanisms. Understanding CNS immunity requires attention to the temporal relationship between the inflammatory response and injury. Acute inflammation is the immediate response that occurs at the initiation of injury. When the BBB is compromised, peripheral blood components such as polymorphonuclear leukocytes have access to the CNS. These cells play part of the defense response and when excessively deployed in the interstitial space they contribute to cell damage. When acute inflammation does not contribute to repair and then cease within a relatively short time period, inflammation becomes chronic and often pathological. Recent advances have begun to define protective, reparative inflammatory responses that set in motion resolution of neuroinflammation thus limiting or abrogating sustained damage. Several potent mediators that modulate the neuroinflammatory response, induce overall homeostasis and attenuate apoptotic neuronal damage are identified.

The Course is aimed at reaching a comprehensive understanding of the cellular and molecular mechanisms, experimental models, and methodological approaches to study neuroinflammation. These will include innovative strategies for emerging targets for clinical translation and pharmaceutical intervention. Moreover, the Course will be a forum where basic and clinical researchers from diverse disciplines can meet, interact, and bring cross-disciplinary insights on new basic findings to the translational stage.

The following are specific topic, which, among others, will be focus of discussion and analysis.

Neurotransmitter Regulation of Microglial Functions: The Locus Ceruleus involvement in Alzheimer Disease
In Alzheimer´s disease, several brain stem nuclei degenerate. Very early during the course of the disease, probably during the mild cognitive impairment (MCI) stage, the locus ceruleus, chief source of norepinephrine in the brain, is already compromized. When, where and why does this nucleus degenerate? The specific role for microglial functioning in locus ceruleus projection area and the consequences for disease progression will be a topic for discussion. Also, the function and modification of nuclear hormone receptors such as the peroxisome proliferator activated receptor gamma and the liver X receptor in physiology and pathophysiology will be addressed. A special emphasis will be put on the fate of these receptors in neurodegeneration and their possible use as therapeutic targets in Alzheimer´s and Parkinson´s disease.

Inflammation and Axonal Degeneration: ALS and MS
Inflammatory pathways are typically activated in neurodegenerative diseases, but sites of inflammation may be a considerable distance from neuronal perikarya. How does local inflammation contribute to axonal and synaptic pathology? Amyotrophic Lateral Sclerosis and Multiple Sclerosis will serve as two examples of distinct pathologies with well-established inflammatory components.

Cell Death Pathways and Neurodegeneration
Neuronal cell death is a late event in most neuropathologies and blocking cell death may not prevent progression of neurological symptoms. Reframing the consideration of cell death in the nervous system to include early stages of axonal degeneration allows a focus on an understanding of the roles played by apoptotic signaling pathways in neurodegenerative diseases and synaptic connectivity.

Control of Chronic Neuroinflammatory diseases: Traditional and Novel Alternative Approaches
Steroids and COX inhibitors have important successes but limitations for chronic use. What are the targets and what novel anti-inflammatory drugs are in the pipeline? Are there promising alternative NSAIDs? Our focus will be on the potential for Omega-3 fatty acids.

Biomarkers of Neuroinflammation
How well can imaging probes detect and monitor active neuroinflammation? What are best CSF biomarkers? Are there any consistent plasma biomarkers? How are these markers altered by CNS diseases? Can any biomarker be used as a surrogate to monitor inflammation?

Neuroinflammation and Neurodegenerative Diseases of Aging
What is the neuropathological and biochemical evidence for a bystander or causal role? We will consider the evidence that the role of innate immune activation is stage-dependent. What is inconsistent and consistent in the epidemiology of NSAIDs for Alzheimer's or Parkinson's Diseases? What are the results of trials aimed at treatment and prevention? What is the best approach to limit chronic inflammation related to aging? Should we use modulatory rather than directly suppressive drugs? Can we break a cycle of chronic inflammation with intermittent use of anti-inflammatory agents that limits toxic effects? Is there any merit to the use of anti-TNFalpha or other passive immunization approaches to chronic inflammatory diseases?

Fever, Sickness Behavior, and Neuroinflammation
Immune "privilege" and immune capacity of the brain will be discussed together with cerebrospinal fluid physiology, transport mechanisms, epiplexus (Kolmer) cells, expression of cell adhesion molecules, microglia, and cytokine receptors on neurons and endocrine glands. Finally, the emerging field of behavioral dysfunction in systemic autoimmunity and inflammation will be addressed analysing the effects of these conditions on the limbic system, cognitive function and brain morphology.

The significance of docosanoid lipid mediators derived from omega-3 essential fatty acids in neuroinflammation
The identification of an endogenous lipid mediators made on demand at the onset of homeostasis disturbances, uncompensated oxidative stress and unresolved neuroinflammation will be discussed. The molecular principles that govern the production and bioactivity of Neuroprotectin D1 (NPD1) in experimental stroke, epilepsy, age-related macular degeneration, Alzheimer's, Parkinson's and other diseases will be highlighted. The following specific aspects will be presented: targeted transcription factors; COX-2; neurotrophins as agonists for NPD1 synthesis; new molecular imaging to open the DHA lipidome; aspirin-triggered NPD1 biosynthesis in the stroke penumbra; NPD1 in the homeostatic regulation of photoreceptor cell integrity; neuroinflammation and resolution in neurodegenerative diseases.

In addition, focus will be placed on:

Microglial response to CNS Trauma: Acute and chronic cellular inflammation
Immunosuppressive effects of CNS injury: Modulation of innate and adaptive immunity
Preclinical and clinical therapeutic trials targeting inflammation following traumatic brain injury: The two-edged sword

Industry's approach to drug discovery in neuroinflammation: reproducibility and wrong statistics.
Microglia as a potential target in Huntington's disease and other pathologies.

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Yoga Gives Back

Written by Kayoko Mitsumatsu

From Posture To Power: Microcredit Changes Lives On Both Sides of the Ocean

We can talk about making change. But affecting real change in the world comes from impacting the lives of individuals. It comes from empowering people to be independent and able to make a living on their own while at the same time being fully integrated in our interdependent global community. Sometimes it takes something that seems to be radical to make this change, but these shifts can be deceptively small. They can be even as small (or as large) as the cost of a Los Angeles Yoga class.

How could this be? In the practice of microcredit, lending seemingly small amounts of money to small-scale entrepreneurs allows them to succeed and change their circumstances. This is the fundamental basis of microcredit’s transformative power; it’s a revolutionary concept in finance. This practice shifts the emphasis from financial transactions being focused only about large loans and large scale businesses, which are out of reach of many one-person operations, institutions and organizations – to lending practices that actually make a positive difference in a person’s life. Microcredit practices based on social justice and empowerment operate through a combination of small-scale loans based on trust and community support, with structured repayment plans and programs that encourage savings. In these situations, people actually have the opportunity to solidify long-term change in their lives.

Dr. Muhammad Yunus and the Yoga Gives Back Team: Joel Bender, Leslie Hendry, Dr. Muhammad Yunus and Kayoko Mitsumatsu (left-right)

In 2006, economist Dr. Muhammad Yunus and the institution he founded, the Grameen Bank, were awarded the Nobel Peace Prize. This award was in recognition of their revolutionary efforts to create this micro-credit model, support sustainable economic practices, and provide an alternative to what were exploitive norms. When a person is caught in a cycle of poverty, they may become trapped in the system, particularly since large banking institutions have historically ignored people without assets or credit histories, who are just starting out and who may not have already proven themselves. Most banks prefer to lend large sums of money that represent a greater profit margin and are set up only for large loans in order to make a profit themselves. And even making it more challenging, people at the bottom of the economic scale worldwide have had to rely on moneylenders charging usurious terms and interest rates to obtain funds to plant the next crop, buy inventory of new equipment, or upgrade a business in any way. Institutions such as the Grameen Bank and their affiliates are offering another approach. It’s one that has significantly impacted millions of people.

As Dr. Yunus described in an exclusive interview with Yoga Gives Back in May, 2009, “We started in 1976, and today within Grameen Bank in Bangladesh, eight million people borrow micro loans, ninety-seven percent of them women.” This represents an enormous potential for change and empowerment that just did not exist on a large scale in this form prior to 1976.

There is a social cycle in economics, and Dr. Yunus explained this: “Poverty is not inside the person. Poverty is forced from outside. Poor people are as capable [a] human being as anybody else. They have the same power and energy, same potential. But they are denied such facilities. They cannot express themselves. Money is one of the most important items missing in their lives. You need a dollar to catch a dollar. You cannot catch a dollar with an empty hand. So, that first dollar, nobody has given to her. So she remains dependent on someone else. She has to be hired, to slave; she has to work to make food available on the table. What we have done, we have put that first dollar into her hands as a banking proposition. Conventional banks never come to the poor people. They go to rich people to make more money. The person who does not have a dollar – she cannot get it. So we did it. We did it in a way that is affordable to her. Because we do not insist on collateral. There is no collateral.”

While that may seem like a radical concept, the Grameen Bank has proven that their success is much more than ideological. Dr Yunus cited statistics for us, “The repayment rate is almost 100%, without collateral or anything. This is the strength of microcredit which is now spread all over the world. There are by now at least 150 million borrowers in the world today. Bu it is still very small comparing to the need. We need more microcredit organizations in the world so that more people can be reached.”

Yoga Gives Back is a 501(c)(3) nonprofit organization begun in LA, with the goal to provide a way for Western Yoga practitioners to give back to India, the birthplace of Yoga, which has given us so much. We’re heeding Dr. Yunus’ call to reach more people through expanded opportunities for and awareness of microcredit and have targeted India and Indian families, women, and would-be entrepreneurs, who would be otherwise stuck in the cycle of poverty that Dr. Yunus described. Yoga Gives Back supports microfinancing operations in India, through the Grameen Foundation, headquartered in Washington, DC. Donations go directly to Grameen Koota, Bangalore, South India and our YGB awareness campaign focuses on the real stories of how poor women are changing their lives with small loans from Grameen Koota.

Ms. Vinatha M Reddy

Grameen Koota was started by visionary teacher and philanthropist, Ms. Vinatha M Reddy (pictured, above) in 1999, who learned about Nobel Peace Recipient Dr Muhammad Yunus’ microfinancing and immediately began exploring ways of replicating his work in her hometown. In 2000, she started providing small microcredit loans, averaging $25.00 a month, to fifty local women. Today, Grameen Koota’s work is reaching out to over 280,000 women in Bangalore, Mysore and many areas of Karnataka state, in South India, making real impact on these women’s lives as well as on the local economy.

Yoga Gives Back

The Los Angeles-based Yoga Gives Back has a worldwide reach and began out of the inspiration and dedication of my Yoga mentor Joel Bender and me. Our group has suddenly started growing almost daily and our mission is shared by a quickly expanding and loving Yoga community.

When I was growing up in Japan, which is a very middle-class society, I had never experienced or seen any real poverty, especially growing up in Tokyo in 1960s and 1970s, when Japan's post-war economic miracle was taking place. Then, I had a chance to live in Brazil in the late 1970s for two years, where as a teenager, I saw the divide between poverty and wealth, the reality of the real slums, kids on the streets begging every time you stopped the car at the traffic light, all very much like India. Social injustice hit me hard.

Once I started Yoga practice and feeling my life being so enriched by it , I felt a need to use my resources to help others. I was producing a documentary on Social Entrepreneurship and learned about microfinancing. I shared this information with Joel [featured in the teacher profile in this month’s issue of LA YOGA] who had been looking for the way he could give back to India since his first visit there – so we teamed up.

When I think about the growth of Yoga Gives Back thus far, I give a lot of credit to the entrepreneurship and volunteer spirit of Americans, willing to embrace and support a new grass roots campaign like ours.

Kayoko Mitsumatsu, co-founder of Yoga Gives Back, is a documentary filmmaker whose films deal with social justice issues, including First They Killed My Father a memoir of a Cambodia’s Killing Fields’ survivor.

A Life Changing Story of Microcredit: Jayashree

Jayashree

Jayashree lives in the suburbs of Bangalore and is married and the mother of two children. We visited her at her humble dirt floor one room home for the first time in 2007. We were touched by her warm smile and most generous hospitality, serving us hot tea and cookies.

Jayashree was born into a very poor family in Bangalore. When she was a child, her family’s financial situation became so severe that she had to drop out of school and work at a garment factory. She toiled throughout her childhood and after she got married at fifteen, her meager earnings had to support her ailing in-laws. She had two children. Her husband’s rickshaw business was not enough to pay her sons’ education or secure food for the family.

In 2007, Jayashree learned from her neighbors about Grameen Koota’s microcredit program and applied for her first loan. She was granted a first loan of 7,000 rupees ($175), and immediately bought her husband’s auto rickshaw. Owning their own rickshaw business increased their income significantly.

Jayashree was able to pay back her entire loan in one year and became eligible for her second loan in 2008. Having proven her diligence, her second loan amount doubled to 15,000 rupees ($375). This time, she bought a sewing machine and started stitching bags. The family’s earnings have now tripled and she is earning 150 rupees ($3.75) a day. In addition, she opened a small shop next to her house to sell her products which is earning her an additional 100 rupees ($2.50) a day.

She is sending her elder son to a medical school. Her son dreams of becoming a doctor and thanks his mother’s business for providing his education, their own home and daily food.

To participate in a Yoga practice where the proceeds support Yoga Gives Back and directly impact the transformation of not only your own life, but that of someone in India, start your Thanksgiving week at Yogaglo, Sunday, November 22, 10:00 A.M. - 12 noon. Some of the teachers include John Sahakian, Felicia Tomasko, Alexandra Aiken and Ally Hamilton; more to be announced. Yogaglo.com; yogagivesback.com.

For more information on Yoga Gives Back or to host a Yoga Gives Back class at your own studio or location, visit: yogagivesback.org or contact yogagivesback@earthlink.net.