Abstracts

Rationale: Neuropharmacological and neurochemical studies in rats suggest that molecules diffuse through the cerebral meninges, in both directions, from the epidural/subdural space into the underlying cortex, and from the cortical tissue into the epidural/subdural compartments. However, these transmeningeal molecule movements, or the effects of such movements have not been visualized with neuroimaging or histological tools. The objective of this study was to examine and visualize the histological impact of epidurally applied NMDA, an agonist for the NMDA-type glutamate receptor, which causes neuronal degeneration in high concentrations.Methods: Under pentobarbital anesthesia, rats were implanted with an epidural cup over the left parietal cortex and with a similar cup over the right parietal cortical region. Upon the completion of the surgical procedure, artificial cerebrospinal fluid (ACSF), as a control solution, was delivered into the left epidural cup, immediately followed by the delivery of a 50 mM NMDA solution into the right epidural cup. The delivery volume was 50 microliter for both solutions. The cups then were closed and secured to the skull with dental acrylic. The anesthesia was discontinued, and the rat was allowed to carry the filled cups for a 24-hour period after surgery. Then the rat was sacrificed, and the animal’s brain was fixed with the transcardial perfusion of 10% formalin. The brain was removed, and tissue blocks were embedded in paraffin, sectioned, and stained with cresyl violet for Nissl substance for the analysis of the histological effects of the epidural ACSF and NMDA deliveries.Results: Cortex treated with NMDA displayed extensive neuronal loss that reflected the diffusion pattern of the drug solution. In the upper cortical layers, neuronal staining for Nissl substance was absent, while in the deeper layers, damaged neurons were observed. Cortical treatment with ACSF resulted in significantly less damage. Only a loss of layer II neurons was noted, that was likely due to the attachment of the epidural cup and application of the solution itself. Nissl substance staining of neurons in the lower cortical layers appeared normal.Conclusions: The results confirmed that drugs applied to the surface of the dura mater do diffuse through the cerebral meninges in the rat, because transmeningeal drug diffusion can be documented and visualized histologically. This supports the idea that the favorable physico-chemical properties of the cerebral meninges allow the development of transmeningeal pharmacotherapy for the treatment of intractable focal epilepsy, using subdural hybrid neuroprostheses, although accompanying unwanted tissue reactions need to be suppressed. (Supported by NYU/FACES.)