At Transpharmation we have established a highly translatable in-vivo electrophysiology telemetry platform in rodents, supporting CNS pharmacodynamic testing of novel compounds.
Good quality sleep is paramount, not just for its fulfilling nature but also for maintaining our mental health and well-being. Sleep gets disrupted in many neuropsychiatric disorders, often before the onset of other symptoms, and its involvement in pathophysiological processes is increasingly understood. In depression, shortened rapid eye movement (REM) sleep latency and increased REM sleep amount are among the most consistent sleep alterations, and it has been proposed that the antidepressant potential of drugs might be related to their capacity for suppressing REM sleep. Psilocybin, a psychedelic compound found in magic mushrooms, has gained much interest recently because of its beneficial effects in treatment resistant depression. At Transpharmation, we have established a highly translatable in-vivo electrophysiology telemetry platform for rodents. We found that psilocybin selectively suppresses REM sleep, both in a phenotypically normal outbred strain and in a rodent model of treatment resistant depression. Thus, drug-induced changes in sleep-wake behaviour may serve as key translational tools in an effort to discover novel therapeutics against the different neuropsychiatric disorders.
Examples of the assays we offer include:
- Transpharmation has a world-class pedigree in Sleep/EEG research. Our expertise in this field stems from research conducted by our management team whilst at GSK, on the central arousal effect of the hypothalamic neuropeptide orexin-A, pivotal in guiding the discovery and development of novel orexin receptor antagonists for a range of sleep disorders. At Transpharmation, we benchmark compounds against clinically relevant standards such as zolpidem and modafinil to evaluate CNS stimulant or sedative/hypnotic properties on sleep/wake cycles in rodents; supporting our clients in the development of novel molecules for a range of therapeutic indications, including sleep disorders.
- The use of qEEG is fundamental in drug discovery given the high predictive and back-translational validity it offers researchers. qEEG methods allow the identification of CNS pharmacodynamic effects of novel test compounds on spectral power frequency bands, recorded from both surface and depth electrodes, providing a highly relevant translational biomarker that can be applied to the clinical setting. For example, QEEG can be used to detect increased gamma oscillations in putative pro-cognitive compounds, benchmarked against gold standards such as donepezil and memantine. Importantly QEEG studies can help to guide strategic decision-making around dose-prediction, PK/PD (concentration-effect) relationships as well as site and mechanism of action for a novel CNS penetrant test compound.
- At Transpharmation, we've applied our expertise in EEG to develop rodent mismatch negativity (MMN) - regarded as one of the most highly-translatable biomarkers for schizophrenia. MMN is a human scalp recorded event related potential (ERP) component elicited by a sound which deviates from a repeating pattern of recent sounds. MMN is generated by a temporo-frontal network including the auditory cortex and is known to be diminished in schizophrenic patients. This disruption can be mimicked by NMDA antagonists (e.g. ketamine) treatment in healthy volunteers. Via collaborations with Cadent and Lundbeck, we have thoroughly validated our MMN protocols with NMDA antagonists such as MK-801, PCP and ketamine in rodents using in-vivo EEG, demonstrating the utility of MMN as a potential translational marker for novel treatments for schizophrenia.
- The auditory steady state response (ASSR) is a highly reproducible auditory evoked EEG response. Disruptions in ASSR are believed to reflect a failure of cortical networks to rapidly integrate auditory sensory information. Generated by synchronous activity in the auditory cortex and reliant on the integrity of cortical GABAergic neural networks, 40Hz ASSR abnormalities are well-characterised in people with schizophrenia.
Examples of end points:
- •REM, non-REM, latency to sleep onset, paradoxical sleep quantification etc.
- •Power spectral band analysis – delta, theta, gamma, beta, alpha frequencies
- •PK analysis
- •Locomotor activity
- •Core body temperature