The pharmaceutical market for the treatment of neurodegenerative disorders will grow by an unprecedented amount over the next ten years. Neurodegeneration accompanies chronic conditions such as Alzheimer's and Parkinson's disease and also more acute states such as from stroke and traumatic head injury.  Stroke is the second most common cause of cardiovascular-related mortality after myocardial infarction. 

The only approved treatment of stroke involves the use of tissue plasminogen activator (Alteplase, rt-PA). This thrombolytic therapy when administered intravenously is however only effective within 3 hours of symptom onset. Only 20-30% of patients arrive at the emergency department within this time frame and, once there, treatment is further delayed by the time taken for evaluation. The National Institute of Neurological Disorders and Stroke (NINDS) has recently made recommendations for the care of patients presenting with signs and symptoms of acute ischemic stroke. These include the evaluation by emergency physician in less than 10 minutes, interpretation of CT scans within 45 minutes, and administration of t-PA within 1 hour after presentation. Although this has increased the number of patients treated, fewer than 10% receive t-PA. Considerable effort still needs to be placed on public education in order to reduce the delay between symptom onset and emergency room presentation. Furthermore t-PA carries a significant risk of hemorrhage further limiting its use.

Given the lack of available treatments of acute stroke, 15-30% of the 600,000 ischemic stroke victims are permanently disabled and 20% require prolonged institutional care. As a result, stroke is the most common cause of long-term serious disability in the US and represents an economic burden similar in scale to myocardial infarction. Acute head injury occurs with a similar frequency to that of stroke.  Approximately 200,000 Americans die each year from their injuries. An additional half million or more are hospitalized and about 10% of the surviving individuals have mild to moderate problems that threaten their ability to live independently. Another 200,000 have serious problems that may require institutionalization or some other form of close supervision. The development of safe and effective acute therapies for stroke patients are thus required. These include thrombolytics with a diminished risk of hemorrhage and also neuroprotective agents. Ideally such therapeutics would be sufficiently safe to allow the possibility of commencing treatment prior to presentation (eg by paramedics) or during evaluation

Over 300 candidate neuroprotective agents have been investigated for the treatment of neurodegenerative disorders (see Neuroprotection - Drugs, Markets and Companies).  In total it has been estimated that the market for neuroprotective agents has now exceeded $5.1 billion rising to $11.5 billion by the year 2010. The most frequently evaluated classes of agent include the free radical scavengers and anti-excitotoxic agents that have direct protective effects on neural cells. 

Once thrombotic occlusion occurs, the ischemic cascade is activated. Within minutes there is a marked increase in excitotoxic glutamate concentration in the affected portion of the brain. This results from a failure in mitochondrial adenosine triphosphate synthesis which in turn causes neuronal depolarization and glutamate release. Increased extracellular potassium also contributes to glutamate elevation by reversing the glutamate uptake transporter.

Glutamate is able to bind the NMDA receptor which causes an increase in its cation conductance. The entry of extracellular calcium entry triggers numerous mechanisms leading to neural damage and death. Blocking the calcium permeability of the NMDA sensitive glutamate has been shown to be neuroprotective in neuronal cell cultures and in animal models of focal brain ischemia but not in animal models of transient global ischemia. Likewise glutamate receptor antagonists have also been of limited benefit. The Mol Pharmacol study highlighted here investigates the possibility of targeting an alternate mechanism of calcium homeostasis, the low voltage activated calcium channel.

The low voltage activated (also known as T-type) calcium channel family includes CaV3.1, CaV3.2 and CaV3.3, channels which are characterized by the ability to sustain a continuous calcium influx in neurons and glia at rest. In their study Nikonendo et al investigated the effect of low voltage activated calcium channel blockers on delayed neural cell death in hippocampal slices following oxygen deprivation. In patients, two major zones of injury are observed following stroke: the core ischemic zone and the ischemic penumbra containing ischemic but still viable cerebral tissue. Maintaining cell survival in the penumbra appears to be the most attractive approach to neuroprotection following stroke since the core is likely unsalvagable. The model employed in the Mol Pharmacol paper resembles the situation in the penumbra following stroke and of note the authors found that limiting calcium levels (through the use of low calcium buffer) reduced delayed cell death. The application of low voltage activated calcium channel blockers, mibefradil (CaV3.2), kurtoxin, nickel and zinc also produced a remarkable neuroprotective effect suggesting that CaV3.2 selective blockers may be of benefit in the acute treatment of stroke.

One of the important findings of the present study is that mibefrandil was neuroprotective when administration was delayed for as long as 3 hours post-ischemia. If similar effects were to be found in patients this will mean that the 20-30% of patients who present within this time period will be suitable for treatment with low voltage activated calcium channel blockers. Moreover if this approach is safe then the proportion of these patients who are treatable may be greater than those that receive t-PA. Furthermore safety would introduce the opportunity for paramedics to administer such agents prior to diagnosis.

Mibefradil was withdrawn from the market in 1998 apparently due to drug interactions as a result of liver enzyme inhibition and so it is unlikely that clinical studies will be conducted to evaluate its benefit to stroke patients. However, the CaV3.2 channel is also sensitive to the anticonvulsant ethosuximide (Zarontin; Pfizer, approved 2001); the antihypertensive and angina treatment, amlodipine; and the diuretic, amiloride. Clinical evaluation of these therapeutics as neuroprotective agents may be of benefit or alternatively the rational design of selective CaV3.2 calcium channel blockers may also be warranted.

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