Cyclophilin-D-inhibiting Cyclosporine-based Drugs
NeuroVive’s core business is the research and development of cyclophilin-D-inhibiting cyclosporine-based pharmaceuticals that protect nerve and heart cells by safeguarding the cell mitochondria against the cascading biochemical imbalances that occur as a result of a tramautic brain injury (TBI). The company is conducting or supporting clinical trials of its cyclosporine-based products NeuroSTAT® and CicloMulsion® in humans, carrying out advanced research and development of new variants of cyclophilin-D-inhibiting cyclosporines, and examining ways of transporting these drugs across the blood–brain barrier to the central nervous system.
NeuroVive is also conducting research and development into other natural and semi-synthetic variants of cyclosporine, and exploring other ways in which the body transports and uses the active agent. There are a number of potential products in this area that have no effect on immune defences but still deliver a positive protective effect on brain-cell mitochondria.
These products could potentially be used to treat prolonged epileptic seizures (status epilepticus), stroke and spinal cord injuries. The research is well advanced, with many of the active agents being studied already having documented use in humans.
Science of cyclosporine’s action in acute injury
There are two stages to acute injuries such as TBI (or reperfusion injury during myocardial infarction). The first stage occurs at the time of injury (typically due to a gunshot, blast, fall, or hit and resulting in either a closed-head or open wound), at which time medical emergency personnel focus on treating the wound or injury and, most importantly, stabilizing the patient’s vital signs.
The secondary stage of damage takes place in the hours and days following the initial trauma, as the injury continues to ripen and worsen. In this secondary stage, a series of cascading intra-cellular biochemical reactions are triggered that can end up causing severe demise of brain cells, brain damage and expanded disability. If this secondary stage can be mitigated, the eventual damage and disability can be greatly reduced, enabling the victim to come closer to full recovery.
Some of the secondary-stage mechanisms believed by researchers to be involved in brain-cell death after TBI include uncontrolled release of signalling molecules (neurotransmitters), cellular calcium overload, inflammation, energy failure, oxidative damage, and the over-activation of enzymes such as calpains and caspases.
All of these are believed to create the intra-cellular and extra-cellular conditions that lead to the destruction of millions of additional brain cells, resulting in extensive damage and disability. Many of these mechanisms are being targeted by a variety of pharmaceutical compounds and medical treatments (such as forcing oxygen into the brain through the use of hyperbaric chambers) currently in various stages of clinical development. Cyclosporine, with its promise of protecting the mitochondria inside brain cells, is perhaps the most promising of these.
Pivotal role of mitochondria
Research confirms that mitochondria, as the cellular energy (ATP) producers inside the brain cells, play a pivotal role in neuronal cell death or survival, and that mitochondrial dysfunction is considered an early event in brain injuries that causes neuronal cell death. The uncontrolled release of signalling molecules, with resulting overstimulation/stress of brain cells and accumulation of high levels of intracellular calcium, may be the initial mechanism that leads to neuronal cell death.
How does this affect brain cells? Simply, increased calcium is rapidly absorbed into the mitochondria (which act as cellular sinks for calcium), and the excessive transport and uptake of calcium negatively impact mitochondrial energy production. This is because the driving force for both ATP production and calcium transport is the “proton motive force” (the proton gradient created over the mitochondrial inner membrane by the respiratory chain), and excessive calcium uptake by mitochondria, in combination with energy failure, lead to the formation of protein channels (pores) in the inner membrane — the induction of the so-called mitochondrial permeability transition (mPT).
The increased permeability of the inner membrane caused by the mPT pores immediately collapses mitochondrial function and structure (i.e., when the pores are opened, the osmotically active inner compartment (matrix) of the mitochondria will attract water and the mitochondria will swell and pop like balloons). In addition to causing the cessation of energy production, upon induction of the mPT the stored calcium and harmful proteins will then be released from collapsed mitochondria, resulting in an avalanche of further mitochondrial collapse, cellular energy depletion, and subsequent cell death. When brain-cell death is repeated millions of times during the cascading biochemical imbalances that characterize the secondary phase, the extent of brain damage and eventual disability is greatly increased.
Protecting the mitochondria by targeting the mPT is a viable neuroprotective approach that has emerged in the last decade. Published research has found that the protein cyclophilin-D is an essential component to opening the mPT pores, and that cyclosporine binds to cyclophilin-D and inhibits the induction of mPT. The result is that mitochondria can absorb much more calcium without collapsing, allowing them to survive. As mitochondria survive to produce energy for the brain cell, fewer brain cells die during the secondary stage. The above process is also the mechanism of cardiac cell death during reperfusion injury occurring in myocardial infarction.