Evaluation of Cannabidiol in Animal Seizure Models by the Epilepsy Therapy Screening Program (ETSP).

Cannabidiol (CBD) is a cannabinoid component of marijuana that has no significant activity at cannabinoid receptors or psychoactive effects. There is considerable interest in CBD as a therapy for epilepsy. Almost a third of epilepsy patients are not adequately controlled by clinically available anti-seizure drugs (ASDs). Initial studies appear to demonstrate that CBD preparations may be a useful treatment for pharmacoresistant epilepsy. The National Institute of Neurological Disorders and Stroke (NINDS) funded Epilepsy Therapy Screening Program (ETSP) investigated CBD in a battery of seizure models using a refocused screening protocol aimed at identifying pharmacotherapies to address the unmet need in pharmacoresistant epilepsy. Applying this new screening workflow, CBD was investigated in mouse 6 Hz 44 mA, maximal electroshock (MES), corneal kindling models and rat MES and lamotrigine-resistant amygdala kindling models. Following intraperitoneal (i.p.) pretreatment, CBD produced dose-dependent protection in the acute seizure models; mouse 6 Hz 44 mA (ED50 164 mg/kg), mouse MES (ED50 83.5 mg/kg) and rat MES (ED50 88.9 mg/kg). In chronic models, CBD produced dose-dependent protection in the corneal kindled mouse (ED50 119 mg/kg) but CBD (up to 300 mg/kg) was not protective in the lamotrigine-resistant amygdala kindled rat. Motor impairment assessed in conjunction with the acute seizure models showed that CBD exerted seizure protection at non-impairing doses. The ETSP investigation demonstrates that CBD exhibits anti-seizure properties in acute seizure models and the corneal kindled mouse. However, further preclinical and clinical studies are needed to determine the potential for CBD to address the unmet needs in pharmacoresistant epilepsy.

The National Institute of Neurological Disorders and Stroke (NINDS) Epilepsy Therapy Screening Program (ETSP).

For over 40 years, the National Institute of Neurological Disorders and Stroke/National Institutes of Health-funded Anticonvulsant Screening Program has provided a preclinical screening service for participants world-wide that helped identify/characterize new antiseizure compounds, a number of which advanced to the market for the treatment of epilepsy. The newly-renamed Epilepsy Therapy Screening Program (ETSP) has a refocused mission to identify novel agents which will help address the considerable remaining unmet medical needs in epilepsy. These include identifying antiseizure agents for treatment-resistant epilepsy, as well as anti-epileptogenic agents that will prevent the development of epilepsy or disease-modifying agents that will ameliorate or even cure established epilepsy and its comorbidities. This manuscript provides an overview of the ETSP's efforts aimed at identifying the next generation of therapeutic agents to further reduce the suffering from and burden of epilepsy.

Therapeutic utility of non-peptidic CRF1 receptor antagonists in anxiety, depression, and stress-related disorders: evidence from animal models.

Adaptive responding to threatening stressors is of fundamental importance for survival. Dysfunctional hyperactivation of corticotropin releasing factor type-1 (CRF(1)) receptors in stress response system pathways is linked to stress-related psychopathology and CRF(1) receptor antagonists (CRAs) have been proposed as novel therapeutic agents. CRA effects in diverse animal models of stress that detect anxiolytics and/or antidepressants are reviewed, with the goal of evaluating their potential therapeutic utility in depression, anxiety, and other stress-related disorders. CRAs have a distinct phenotype in animals that has similarities to, and differences from, those of classic antidepressants and anxiolytics. CRAs are generally behaviorally silent, indicating that CRF(1) receptors are normally in a state of low basal activation. CRAs reduce stressor-induced HPA axis activation by blocking pituitary and possibly brain CRF(1) receptors which may ameliorate chronic stress-induced pathology. In animal models sensitive to anxiolytics and/or antidepressants, CRAs are generally more active in those with high stress levels, conditions which may maximize CRF(1) receptor hyperactivation. Clinically, CRAs have demonstrated good tolerability and safety, but have thus far lacked compelling efficacy in major depressive disorder, generalized anxiety disorder, or irritable bowel syndrome. CRAs may be best suited for disorders in which stressors clearly contribute to the underlying pathology (e.g. posttraumatic stress disorder, early life trauma, withdrawal/abstinence from addictive substances), though much work is needed to explore these possibilities. An evolving literature exploring the genetic, developmental and environmental factors linking CRF(1) receptor dysfunction to stress-related psychopathology is discussed in the context of improving the translational value of current animal models.