Mechanism of Action and Clinical Potential of Fingolimod for the Treatment of Stroke

Fingolimod already has this positive research needing more followup: Already approved for MS, so your doctor being an innovative sort will likely use this as an off-label use for stroke. That will never occur, you will just need to deal with the fact your doctor is doing nothing in the first week to save all your dying neurons.(neuronal cascade of death)

FTY720 Preserves Blood-Brain Barrier Integrity Following Subarachnoid Hemorrhage in Rats

The latest here:

Mechanism of Action and Clinical Potential of Fingolimod for the Treatment of Stroke

Wentao Li¹, Haoliang Xu² and Fernando D. Testai¹*

• ¹Department of Neurology and Rehabilitation, University of Illinois College of Medicine, Chicago, IL, USA
• ²Department of Pathology, University of Illinois College of Medicine, Chicago, IL, USA

Fingolimod (FTY720) is an orally bio-available immunomodulatory drug currently approved by the FDA for the treatment of multiple sclerosis. Currently, there is a significant interest in the potential benefits of FTY720 on stroke outcomes. FTY720 and the sphingolipid signaling pathway it modulates has a ubiquitous presence in the central nervous system and both rodent models and pilot clinical trials seem to indicate that the drug may improve overall functional recovery in different stroke subtypes. Although the precise mechanisms behind these beneficial effects are yet unclear, there is evidence that FTY720 has a role in regulating cerebrovascular responses, blood–brain barrier permeability, and cell survival in the event of cerebrovascular insult. In this article, we critically review the data obtained from the latest laboratory findings and clinical trials involving both ischemic and hemorrhagic stroke, and attempt to form a cohesive picture of FTY720’s mechanisms of action in stroke.

Introduction

Fingolimod (FTY720) is an orally bio-available immunomodulatory drug unique for its reversible leukocyte sequestration properties. In 2010, it was approved by the FDA for the treatment of multiple sclerosis (MS) (1, 2).

Given the current understanding of the role of the immune system in the pathophysiology of brain injury in cerebrovascular diseases, there is now significant interest in the potential benefits of FTY720 on stroke outcomes. Several groups have independently evaluated its effects in rodent models of brain ischemia and intracerebral hemorrhage (ICH). More recently, pilot clinical trials have been conducted demonstrating promising results, albeit in small populations (3–5). Taken together, these studies seem to indicate that administration of FTY720 results in overall improved functional recovery in different stroke subtypes.

The precise mechanisms behind these beneficial effects are still under investigation. FTY720 is a partial sphingosine-1-phosphate (S1P) agonist with immunomodulatory properties that regulates cerebrovascular responses, blood–brain barrier (BBB) permeability, and central nervous system (CNS) cell survival (6, 7). In this article, we will organize these elements and attempt to form a cohesive picture of FTY720’s mechanisms of action in stroke, and critically review the data obtained from recent clinical trials.

Role of the Immune System in Stroke Progression

Immunomodulation is a well-characterized effect of FTY720 and is thought to mediate some of the beneficial effects seen in stroke models. In order to understand the extent to which the immune system impacts the evolution of stroke outcomes, we will sketch a proposed model of the immune cascade following ischemic insult.

In the immediate aftermath of an ischemic event, complement activation, clot formation, and oxidative stress result in direct damage to local vasculature. Endothelial cells die and detach, interrupting the integrity of the BBB and exposing sub-endothelial antigens. Immune cells adhere to the vessel wall and upregulate the expression of chemoattractant and adhesion molecules that lead to the infiltration of the brain parenchyma by the innate immune system.

A combination of neutrophils, monocytes, and macrophages, this innate immune system further contributes to vascular compromise and early inflammation. One well-documented process is through the release of matrix metalloproteinases (MMPs) by the immune cells, particularly MMP-9, which contributes to the breakdown of the BBB with the resultant edema and growth of the infarcted area (8).

In the parenchyma, glial cells are also activated by the inflammation and damage-associated molecular patterns (DAMPs) released from dying neurons. These reactive astrocytes and microglia further stimulate the recruitment of leukocytes, which release their own pro-inflammatory chemokines, perpetuating a cycle of vascular damage, inflammation, and cell death (9).

The second, adaptive phase of the immune response is mediated predominantly by effector T cells, which are stimulated by DAMPS and brain-specific antigens released upon neuronal cell death (10). These T cells mobilize to the injured regions of the brain, infiltrating a compromised BBB to release pro-inflammatory cytokines, including IFN-γ, resulting in a delayed neurotoxic effect (11, 12). Of note, brain-specific antigens were identified in cervical nodes and palatine tonsils of animals with cerebral ischemia and stroke survivors. Interestingly, some of these antigens were associated with infarct volume and survival. While these studies need to be replicated in larger cohorts, they suggest the participation of peripheral lymphoid tissue in stroke-associated inflammation and outcomes.

Lastly, the inflammatory process is brought to an end via a combination of B cells and regulatory T cells. The latter acts through IL-10, which in combination with TGF-β produced by local macrophages, suppresses further helper T-cell-induced inflammation, and promotes the regeneration of remaining viable neurons (13, 14).

A reduction in various components of the innate and adaptive immune response have been associated with better stroke outcomes. Clinically, a lower ratio of CD14+ pro-inflammatory monocytes to CD16+ reparative monocytes has been correlated with better acute and long-term functional outcomes (15). Similarly, decreased complement activation, specifically the reduced expression of C3, C4, and C-reactive protein, has been associated with better recovery at 3 months post-stroke (16). Experimentally, inhibition of CD8+ and CD4+ T-cell migration into the CNS and direct disruption of CD8+ cytotoxicity has led to reduced infarct volume and post-ischemic inflammation (17). Disruption of the DAMPs-activated γδT cells have also resulted in decreased infarct size and better functional recovery in mice (18). Finally, direct delivery of B cells and IL-10 to the brain in animal models have resulted in a reduction of inflammatory cytokines produced by effector T cells and a reduction of infarct size (19, 20).

Fingolimod and Stroke-Related Mechanisms of Action

Pharmacology

Isaria sinclairii, otherwise known as “winter-insect and summer-plant,” is a fungus that has been used in traditional Chinese medicine for over 300 years. Classically prescribed as a panacea for multiple ailments, it produces an atypical amino acid myriocin (ISP-1) that blocks the synthesis of sphingolipids. This chemical compound has since been modified into fingolimod, also known as FTY720 (21). In Western Medicine, FTY720 initially showed promise in preventing ischemic–reperfusion injury following organ transplant, but failed clinical trials due to the development of acute macular edema in some patients (22, 23). In 2010, it became the first oral disease modifying drug approved for treatment of MS (6). In its base form, FTY720 is an orally bio-available, lipophilic molecule that readily crosses the BBB and steadily accumulates in the CNS white and gray matter (24). It bears a structural similarity to sphingosine and is reversibly phosphorylated primarily by Sphingosine-Kinase 2 (SphK2) and, to a lesser extent, by SphK1 (25). In its activated form, FTY720-phosphate is a sphingosine-1-phosphate (S1P) analog that binds to cell membrane G-coupled S1P receptors (S1PR) S1PR1, 3, 4, and 5, but not S1P2 (26). With the exception of S1PR4, these receptors are ubiquitously distributed in the CNS (Table 1). In addition to its action on cell surface receptors, FTY720 regulates the synthesis of different bioactive sphingolipids and, together with S1P, regulates gene expression via epigenetic mechanisms (Figure 1). The half-life of FTY720 averages ~9 days and its pharmacology is not sensibly affected by age, weight, sex, or ethnicity (27).