Current Approaches to Monitor Macromolecules Directly from the Cerebral Interstitial Fluid

Abstract

Gaining insights into the pharmacokinetic and pharmacodynamic properties of lead compounds is crucial during drug development processes. When it comes to the treatment of brain diseases, collecting information at the site of action is challenging. There are only a few techniques available that allow for the direct sampling from the cerebral interstitial space. This review concerns the applicability of microdialysis and other approaches, such as cerebral open flow microperfusion and electrochemical biosensors, to monitor macromolecules (neuropeptides, proteins, …) in the brain. Microdialysis and cerebral open flow microperfusion can also be used to locally apply molecules at the same time at the site of sampling. Innovations in the field are discussed, together with the pitfalls. Moreover, the ‘nuts and bolts’ of the techniques and the current research gaps are addressed. The implementation of these techniques could help to improve drug development of brain-targeted drugs.

In vivo monitoring of brain pharmacokinetics and pharmacodynamics with cerebral open flow microperfusion

“…Several techniques are currently available for measuring cerebral compound concentrations in preclinical studies (Custers et al, 2022).…”

“…Several techniques are currently available for measuring cerebral compound concentrations in preclinical studies (Custers et al., 2022). The best established and still most common method for evaluating the concentration of a compound inside the brain tissue is taking biopsies.…”

Neurofilament light chain: A possible fluid biomarker in the intrahippocampal kainic acid mouse model for chronic epilepsy?

“…This model has previously been optimized in our laboratory. 19,20 In the current experiments, NfL levels were determined directly in the cerebral ISF by using cerebral open flow microperfusion (cOFM) as sampling technique (for more information, see Birngruber et al 21 and Custers et al 22 ) as well as in CSF and plasma. Previous (pre)clinical studies in various disease models have investigated NfL levels in CSF and blood, 23 but successful determination 24 and chronic follow-up 25 of NfL directly from the cerebral ISF • The intrahippocampal kainic acid mouse model of temporal lobe epilepsy is used to assess the potential of NfL as a possible diagnostic and response fluid biomarker • ISF and plasma NfL levels are higher during status epilepticus compared to sham mice and are lowered when status epilepticus is stopped • In the chronic phase with spontaneous seizures, higher NfL levels could only be detected in ISF and cerebrospinal fluid samples, not in plasma have rarely, if ever, been reported in literature.…”

“…This model has previously been optimized in our laboratory 19,20 . In the current experiments, NfL levels were determined directly in the cerebral ISF by using cerebral open flow microperfusion (cOFM) as sampling technique (for more information, see Birngruber et al 21 and Custers et al 22 ) as well as in CSF and plasma. Previous (pre)clinical studies in various disease models have investigated NfL levels in CSF and blood, 23 but successful determination 24 and chronic follow‐up 25 of NfL directly from the cerebral ISF have rarely, if ever, been reported in literature.…”

Brain-Targeted Drug Delivery

“…These anti-tau and bispecific mAbs are able to induce receptor-mediated transcytosis in capillary endothelial cells of the BBB and might represent a solution for Aβtargeting therapies. Lastly, Custers et al reviews the literature on the current approaches to detect and monitor macromolecules in the brain directly from the cerebral interstitial fluid [12]. Direct sampling from the cerebral interstitial space can be done via a few techniques such as microdialysis, cerebral open flow microperfusion and electrochemical biosensors.…”