Histaminergic Basis of Central Fatigue in Multiple Sclerosis - A Novel Therapeutic Approach
Abstract
Objective: Understanding the mechanisms of causation of fatigue in multiple sclerosis (MS) and developing new treatments is the focus of this proposal. Specifically, in this proposal, we will raise histamine in the brains of patients with MS, based on the idea that brain histamine levels are low in patients with MS and fatigue. Rationale: Why is histamine in the brain important? Previous work by us identified modafinil as an effective treatment of fatigue in some but not all patients with MS. Recent studies have identified that modafinil binds to a select group of nerve cells that use histamine as the main chemical to communicate to other nerve cells (neurotransmitter). There are approximately 67,000 nerve cells in this location known as the tuberomammillary nucleus, and these nerve cells communicate to select parts of the brain and spinal cord by using histamine as their main neurotransmitter. There are many reasons to believe that these nerve cells control a variety of basic functions, such as level of energy in addition to other functions, namely wakefulness and sleep, hunger, cognition, and endocrine function through the pituitary gland. How can we raise brain histamine levels? Administration of histamine directly into blood will not help the brain since there is a very effective barrier between the blood and the brain that will deny access of histamine to the brain. On the other hand, l-histidine, a building block of all proteins (amino acid) has free access to the brain. However there are many more cells outside the brain that can use and deplete l-histidine before it has a chance to get to the brain. The chemical (enzyme) that promotes this conversion is histidine decarboxylase, which is present in a number of cells called mast cells. We will block this enzyme outside the brain by using a drug called lodosyn. This drug will prevent the conversion of l-histidine to histamine outside the brain while permitting conversion within the brain because lodosyn cannot cross the blood-brain barrier. What are the experiments we are proposing? In the first set of experiments, we will identify in normal healthy volunteers ("Phase 1") the dose of L-histidine that is safe and effective in raising the levels of histamine in the brain. These volunteers will take lodosyn and l-histidine in the prescribed doses twice daily. The protocol will gradually increase l-histidine dose and assess how well the medicine is tolerated by each subject using extensive questionnaires. Every subject will also undergo a lumbar puncture at the end of each period. The best tolerated dose from this Phase 1 study will be used in the Phase 2 clinical trial. Levels of histamine in the spinal fluid, which is an indirect marker of brain histamine, will also be measured. In the "Phase 2 studies," we will examine in blinded trials in MS patients with fatigue, the effects of the identified dose of l-histidine in improving fatigue. Patients will be randomly assigned to treatment or placebo for 2 weeks. Then they will go through the "washout phase" when they are on no treatment. After that, those who were on previously on drug will cross over to the placebo arm and those who were on placebo will move over to the treatment arm. In this design, every patient is assured of being on active treatment at some point in the study. Lumbar punctures at the end of each phase are encouraged but not mandated. Fatigue levels, quality of life measures, and a variety of other metrics will be examined. What is the ultimate applicability and impact of this research? Fatigue is a severe and sometimes disabling symptom of MS. It has been reported in over 70% of patients and in over half those patients it can be a disabling symptom that may lead to unemployment. The proposed approach to treat fatigue is completely novel and not only useful in identifying treatment modalities but also in improving our understanding of mechanisms of fatigue i
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610462
Entities
People
- Kottil Rammohan
Organizations
- United States Army
- University of Miami