Acute neurodegeneration caused by stroke or trauma as well as more chronic disease resulting from Alzheimers’s disease or Parkinson’s disease has inflammatory and direct neurotoxic components. There is an urgent need for improved neuroprotective agents driving the development of a market expected to be worth $11.5 billion by the year 2010 (see Neuroprotection - Drugs, Markets and Companies). The transcription factors, NF-Kappa B and AP-1 are though to play an important role in both the transcription of inflammatory mediators and cell survival. Bayer Healthcare researchers have developed synthetic derivatives of the phytogenic therapeutic, Rocaglaol. The lead compound is shown here to have broad ranging anti-inflammatory and neuroprotective active resulting is therapeutic activity in models of head injury and Parkinson’s disease.

The pharmaceutical market for the treatment of neurodegenerative disorders will grow by an unprecedented amount over the next ten years. Alzheimer's and Parkinson's disease will lead to an expansion of the multi-billion neurodegenerative market. Parkinson's disease, a chronic and progressive neurological condition, affects approximately 1.5 million people in the US alone (see our editorial on Parkinson's Disease). The prevalence of Parkinson's disease is second only in the neurodegenerative disorders to Alzheimer's disease. The number of sufferers of this condition is expected to grow from 16 million patients to 21 million by 2010 in the seven major pharmaceutical markets. Sales of Alzheimer's therapeutics are set to reach $6.1 this year, increasing to $ 7.8 billion by 2010 (Alzheimer disease - new drugs, markets and companies).

In addition to being caused by chronic disease, neurodegeneration also results from stroke and traumatic head injury. Stroke is the second most common cause of cardiovascular-related mortality after myocardial infarction. Given the lack of effective treatments of stroke available past the first few hours after the onset of symptoms, 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.

Over 300 candidate neuroprotective agents have been investigated for the treatment of chronic and acute neurodegenerative disorders (see Neuroprotection - Drugs, Markets and Companies). The most frequently evaluated classes of agent include the free radical scavengers and anti-excitotoxic agents that have direct protective effects on neural cells. Accumulating evidence implicates inflammatory processes in the development of a number of neurodegenerative diseases. The development of anti-inflammatory agents for the treatment of both traumatic head injury and chronic conditions such as Alzheimer’s and Parkinson’s disease thus represents a growing focus for the drug development sector. 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 featured Mol Pharmacol study described a synthetic anti-inflammatory derivative of the natural product rocaglaol developed by Bayer Healthcare researchers. Rocaglaol can be isolated from the leaves and blossoms of Aglaia species, extracts of which are used in natural medicine in the southeast asian region and have been reported to exhibit anti-inflammatory and anti-tumor activity. The reduction in tissue inflammation and neuronal cell death produced by this derivative, termed compound A, resulted in significant neuroprotection in animal models of acute and chronic neurodegeneration.

Nuclear transcription factors such as NF-kappaB and AP-1 play a key role in coordinating gene expression in response to multiple stimuli. AP-1, composed of homo- or heterodimers of the Jun, Fos, activating transcription factor, or Maf families, is involved in various aspects of cell proliferation and differentiation and also contributes to genomic reprogramming during inflammation. NF-kappaB is present in the cytosol as an inactive complex with I-kappaB; their dissociation results in the migration of NF-kappaB to the nucleus. This results in the induction of multiple genes encoding inflammatory mediators and also regulates pathways involved in apoptosis and oncogenesis. A common feature of many acute and chronic neurodegenerative diseases, including traumatic and ischemic brain injury, Alzheimer's disease and Parkinson's disease, is the presence of a localized inflammatory tissue response as well as activation of NF-kappa B and elements of the AP-1 pathway both in neurons and glial cells. Targeting these pathways may limit neurodegeneration both through the inhibition of inflammation and direct effects on neural survival.

In their paper Fahrig et al report that compound A reduced chemokine release and the induction of iNOS and COX-2 by IL-1- and/or LPS-stimulated glial cells, immunocytes that are directly involved in immune reactions within the brain. The authors investigated the mechanism of action of these anti-inflammatory effects and report that compound A prevented LPS-induced nuclear accumulation of NF-kappaB as well as expression and phosphorylation of elements of AP-1 (c-Jun).

In addition to determining the anti-inflammatory activity of compound A, Fahrig et al investigated its direct effect on neural cell death. Using a model of dopaminergic neuronal cell damage the authors report that compound A reduced MPP-induced mesencephalic cell toxicity. A similar effect was observed in vivo when mice were challenged with the precursor of MPP+, MPTP. This model is an accepted model of Parkinson’s disease and at 1 micro g/kg (ip) compound A was able to reduce neural toxicity by 50%. In a model of traumatic brain injury, compound A significantly reduced infarct volume, albeit with slightly less potency (10 micro g/kg iv reduced brain damage by 48%).

The present study therefore characterizes a candidate therapeutic for the treatment of both chronic and acute neurodegenerative disorders. The mechanism of action involves transcription factors that contribute directly and indirectly to the neurodegenerative process. The balance between direct neuroprotective and indirect anti-inflammatory activity of compound A is unclear however its potential effect on both of these components of neurodegenerative disease suggests that compound A or further rocaglaol derivatives hold considerable promise for the treatments including traumatic brain injury, Parkinson’s disease and Alzheimer’s disease.

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Entry date Monday, April 11, 2005

Mol Pharmacol. 2005 Feb 16; [Epub ahead of print]

 

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