A Combination Therapy of 17β-Estradiol and Memantine Is More Neuroprotective Than Monotherapies in an Organotypic Brain Slice Culture Model of Traumatic Brain Injury

Abstract

Combination therapies are a promising therapeutic option for traumatic brain injury (TBI) owing to the clinical failure of monotherapy treatments, such as progesterone. Organotypic hippocampal slice cultures (OHSCs) from Sprague-Dawley rats were subjected to an in vitro TBI, and the neuroprotective effects of 17β-estradiol (E2) or memantine (MEM) monotherapies were quantified. Several combination treatments at different concentrations of both drugs were tested, with 100 pM of E2 and 10 μM of MEM statistically and significantly reducing cell death over either monotherapy when administered immediately after injury. This combination was also significantly neuroprotective when administered 1 h postinjury, possibly supporting future in vivo studies. Further, we hypothesized that this synergy could be the result of MEM blocking a potentially deleterious effect of E2, specifically E2 enhancement of N-methyl-D-aspartate (NMDA) currents. Evoked electrophysiological responses in OHSCs were potentiated by E2 treatment, whereas this potentiation was significantly reduced by MEM. In conclusion, a combination therapy of E2 and memantine was significantly more neuroprotective than both monotherapy treatments, and this synergy may be the result of MEM blocking a deleterious E2-mediated enhancement of NMDA receptors.

Bioorthogonal chemical imaging of metabolic activities in live mammalian hippocampal tissues with stimulated Raman scattering

“…The same platform can be potentially applied to other brain disease or injury models based on organotypic brain tissue culture. It is expected that our technique will be a powerful tool to visualize global downstream metabolism after initial signaling events and to identify key regions of interest for therapeutic development in treating concussion-related head injury, especially if combined with small molecule screening61.…”

“…High speed video (MotionPro, Redlake, Pasadena, CA) is used to verify tissue deformation by image analysis at 1000 frames per second. Lagrangian strain of the tissue is determined by calculating the deformation gradient tensor by locating fiduciary markers on the tissue slice before and at maximal stretch using custom MATLAB (MathWorks, Natick, MA) scripts61.…”

Drug-Drug Interaction Prediction on a Biomedical Literature Knowledge Graph

“…The predicted drug-pairs that were validated on the new database can be seen in Table 3. As an example of the AD drugs, Estradiol is a form of estrogen used to treat menopause symptoms and its relation with Memantine (medication for mild-to-severe AD) has been thoroughly studied [7]. Taking into account the interaction with Rivastigmine (another medication for moderate AD), our model has captured the possible DDIs that emerge with hormone therapy trials after menopause and the adverse effects they can cause in Alzheimer's patients.…”

Innovations in 3D Tissue Models of Human Brain Physiology and Diseases

“…[57,58] Brain slice models of TBI also provide a useful tool for screening therapeutic strategies, and several candidates have already been identified, such as hypothermia, [59] inert gases, [60] sodium calcium exchanger blockers, [61,62] and glutamate receptor blockers. [63] Although hypothermia has been used in the treatment for TBI, a recent review did not identify improvement in clinical outcomes. [64] Because tumor metastasis to the brain and brain tumor invasiveness directly correlates to poor prognosis, many researchers study tumor cell migration in vitro.…”