Traumatic brain injury (TBI) is one of the main causes of mortality among military personnel, children, young adults and athletes. Medicortex Finland has adopted a novel approach to attenuate secondary damages related to traumatic brain injury and stroke. TBI is manifested by early events and delayed secondary alterations. The latter include: mitochondrial dysfunction, lipid degradation and peroxidation and blood-brain barrier (BBB) disruption. This is followed by raised intracellular calcium influx and activation of proteases, resulting in axonal swelling, disconnection and degeneration. Pro-inflammatory factors are produced and secreted by local and infiltrated immune system cells, promoting the development of the inflammatory process. This series of events results in various neurological deficits. Since the degenerative process is mediated by multiple biological reactions, agents that target a single pathway are ineffective.
Method
Medicortex presents a novel family of new chemical entities that cross the BBB, each possessing a penetrating head with a chemical spacer and two or more of the following properties: binding of free metal ions, anti-oxidation, anti-inflammation, and/or anti-bacterial. The lead compounds will be selected according to their solubility, stability and toxicity. In vitro and in vivo studies are conducted in order to explore the efficacy of the molecules as neuroprotective agents under different insults and to attenuate neural damage, utilising animal models of cortical impact brain injury.
Results
The first compound, TBI-466, was tested by repeated injection at different concentrations and was found to be safe.
Conclusions
Taken together, Medicortex's multi-functional drug agents will target biochemical pathways occurring at different time points post-injury, thereby attenuating and even preventing secondary TBI-associated neurological dysfunction and neuronal cell death.
We have established previously that rat bone tissue, as well as rat and human-derived bone cells in culture, show a sex-specific response to gonadal steroids in stimulation of the specific activity of the BB isozyme of creatine kinase (CK) and DNA synthesis. This response could be modified by manipulation of the endocrine environment during early stages in rat development. To further examine the influence of changing hormonal steroid milieu and vitamin D status on the action of gonadal steroids in developing bone tissue, we used two models of ectopic bone formation: demineralized tooth matrix (DTM) implanted under the skin, and femoral bone marrow (BM) transplanted under the kidney capsule of a syngeneic recipient mouse. The response to gonadal steroids in ossicles developed from implanted DTM depended on the recipient's gender; injection of estradiol 17beta (E2; 5 microg) into young female mice 21 days after DTM implantation increased, 24 h later, CK activity in the newly formed ossicles by approximately 60%, whereas injection of dihydrotestosterone (DHT; 50 microg) had no effect on CK activity. In contrast, in male mice, DHT but not E2 increased CK activity in the ossicles by approximately 50%. This sex-specific response was abolished in gonadectomized mice resulting in a similar response of the ossicles to both E2 and DHT. When DTM was implanted into vitamin D- deficient female mice, there was a lower basal CK activity and a significantly diminished response to E2 in the newly formed bone tissues. When BM, which contains mesenchymal and stromal cells and committed osteoprogenitor cells, was transplanted into 6-week-old intact or gonadectomized female or male mice, the response of the newly formed bone ossicles, 21 days after transplantation, to E2 or to DHT was according to the gender of the donor. Bone formed from BM obtained from female mice responded to E2 only and those formed from male BM responded to DHT only. Ossicles developed from BM obtained from gonadectomized mice showed lack of response to either gonadal steroid. Furthermore, only approximately 25% of the BM transplants obtained from castrated (CAST) male donors developed into ossicles. Ossicles formed from BM obtained from vitamin D-deficient female donors showed lack of response to gonadal steroids. These findings suggest that the manipulation of the hormonal milieu in early stages of the differentiation sequence of bone cells modifies the subsequent selective responsiveness of the developing bone tissue to gonadal steroids.
