Neuroinflammatory pathways as treatment targets in epilepsy

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Epilepsy is a chronic disorder affecting around 65 million people worldwide. This neurological disease is characterized by an enduring propensity for generation of seizures, which are usually treated with seizure medications. However, around 30% of the epilepsy patients (~20 million) do not respond to current treatments, which highlights the need of identifying novel targets for the treatment of this condition.

Several hypotheses (transporter hypothesis, gene variant hypothesis…) have been suggested trying to explain the reasons why this large number of epilepsy patients does not respond to current medications, but up to date none theory alone fully explains the neurological basis of epilepsy pharmacoresistance. Nevertheless, in the recent years, the role of neuroinflammation in epilepsy and phamacoresistant epilepsies has emerged as a new theory and is gaining attention as a novel target for the treatment of this disease. In this regard, there is an increasing consensus about the fact that neuroinflammation seems to be a common hallmark in all epilepsy syndromes, including refractory epilepsy, which fact paves the way for developing novel new drugs or pharmacological interventions.

Neuroinflammation is considered to be a normal response that helps to maintain homeostasis, thereby enabling the central nervous system to cope with an insult (seizure) and balance the enhanced metabolic demand during increased neuronal activity. However, a neuroinflammatory response that is protracted or too intense can become maladaptive, thereby leading to cellular dysfunction. An increased understanding of neuroinflammatory mechanism in epilepsy has identified cellular and molecular targets for new mechanistic therapies or existing anti-inflammatory drugs that could overcome the limitations of current medications, which provide only symptomatic control of seizures.

In this scenario, Professor Annamaria Vezzani et al. from the Mario Negri Institute for Pharmacology Research (Italy) have published this month in Nature Reviews Neurology a comprehensive review about entitled “Neuroinflammatory pathways as treatment targets and biomarkers in epilepsy” which highlights the pivotal role of inflammation in epilepsy. This review provides an update and in depth discussion of specific inflammatory pathways proposed to be crucial in the underlining molecular mechanism of epilepsy, paying special attention to the pathways in which advances in knowledge have been made recently: the interleukin-1 receptor/toll-like receptor, the arachidonic acid-prostanoid cascade, oxidative stress and transforming growth factor-β signaling associated with blood-brain barrier dysfunction. The review describes in detail the role of each pathway in epilepsy and how these are activated. In addition to this, potential targets within the inflammatory pathways are suggested. These suggestions are supported by clinical studies with target-specific anti-inflammatory treatments which showed a promising reduction in seizure activity in drug-resistant epilepsy patients. In addition to the discussion on the development of new treatments for epilepsy, the review also describes the potential of the inflammatory mediators involved in these pathways as diagnostic, prognostic and predictive biomarkers for epilepsy, which could be instrumental for patient stratification in clinical trials and patient monitoring.       

The review concludes indicating that some anti-inflammatory interventions might offer neuroprotection when applied in a timely manner. In addition to this anti-inflammatory interventions might also improve neurological comorbidities of epilepsy, such as cognitive deficits and depression, which can severely impair the quality of patients.    

 

At Iproteos, we believe in the advantages of inhibiting gelatinases to reduce not only the neuroinflammation process but also the advance of epileptogenesis.  For that reason, our epilepsy program was aimed to discover selective compounds inhibiting brain gelatinases.

Up to the date, our lead candidate IPR-179 has shown impressive activity in epilepsy models showing that by inhibiting gelatinases we are able to stop the progression of epileptogenesis. For more information about how our epilepsy program, please feel free to contact us.

 

*Figure from A. Vezzani, S. Balosso and T. Ravizza. Nature Reviews Neurology 2019;15:459-472.

 

References

 

Vezzani A ., Balosso S. and Ravizza T. Neuroinflammatory pathways as

treatment targets and biomarkers in epilepsyNature Reviews Neurology.  2019; 15:459-472.