Traumatic brain injury (TBI) induces blood-brain barrier (BBB) disruption, which contributes to secondary injury of brain tissue and development of chronic cognitive decline. However, single mild (m)TBI, the most frequent form of brain trauma disrupts the BBB only transiently. We hypothesized, that co-morbid conditions exacerbate persistent BBB disruption after mTBI leading to long term cognitive dysfunction. Since hypertension is the most important cerebrovascular risk factor in populations prone to mild brain trauma, we induced mTBI in normotensive Wistar and spontaneously hypertensive rats (SHR) and we assessed BBB permeability, extravasation of blood-borne substances, neuroinflammation and cognitive function two weeks after trauma. We found that mTBI induced a significant BBB disruption two weeks after trauma in SHRs but not in normotensive Wistar rats, which was associated with a significant accumulation of fibrin and increased neuronal expression of inflammatory cytokines TNFα, IL-1β and IL-6 in the cortex and hippocampus. SHRs showed impaired learning and memory two weeks after mild TBI, whereas cognitive function of normotensive Wistar rats remained intact. Future studies should establish the mechanisms through which hypertension and mild TBI interact to promote persistent BBB disruption, neuroinflammation and cognitive decline to provide neuroprotection and improve cognitive function in patients with mTBI.

Rationale: There are controversial pieces of evidence whether combination therapies using memantine and cholinesterase inhibitors are beneficial over their monotreatments. However, results of preclinical studies are promising when memantine is combined with agonists and allosteric modulators of the alpha7 nicotinic acetylcholine receptor (nAChR). Objectives: Here, we tested the hypothesis that cognitive enhancer effects of memantine can be potentiated through modulating alpha7 nAChRs in a scopolamine-induced amnesia model. Methods: Monotreatments, as well as co-administrations of selective alpha7 nicotinic acetylcholine receptor agonist PHA-543613 and memantine were tested in the Morris water maze task in rats. The efficacy of the co-administration treatment was observed on different domains of spatial episodic memory. Results: Low dose of memantine (0.1 mg/kg) and PHA-543613 (0.3 mg/kg) successfully reversed scopolamine-induced short-term memory deficits both in monotreatments and in co-administration. When recall of information from long-term memory was tested, pharmacological effects caused by co-administration of subeffective doses of memantine and PHA-543613 exceeded that of their monotreatments. Conclusion: Our results further support the evidence of beneficial interactions between memantine and alpha7 nAChR ligands and suggest a prominent role of alpha7 nAChRs in the procognitive effects of memantine.

Repetitive mild traumatic brain injuries (TBI) impair cognitive abilities and increase risk of neurodegenerative disorders in humans. We developed two repetitive mild TBI models in rats with different time intervals between successive weight-drop injuries, and assessed cognitive performance and biomarker profiles. Rats were subjected to repetitive Sham (no injury), single mild (mTBI), repetitive mild (rmTBI – 5 hits, 24 h apart), rapid repetitive mild (rapTBI – 5 hits, 5 min apart) and single severe (sTBI) TBI. We assessed cognitive performance 2 and 8 weeks after TBI in the novel object recognition test (NOR), and 6-7 weeks after TBI in the water maze (MWM). Acute immunohistochemical markers were checked 24 h after TBI, and blood biomarkers were measured with ELISA 8 weeks after TBI. In the NOR, both rmTBI and rapTBI showed poor performance at 2 weeks post-injury. At 8 weeks post-injury, the rmTBI group still performed worse than the Sham and mTBI groups, while the rapTBI group recovered. In the MWM, the rapTBI group performed worse than Sham and mTBI. Acute APP and RMO-14 immunohistochemistry showed axonal injury at the pontomedullary junction in the sTBI, but not in other groups. ELISA showed increased serum GFAP levels 8 weeks after sTBI, while no differences were found between the injury groups in the levels of phosphorylated-tau and S100β. Results suggest that the rmTBI protocol is the most suitable model for testing cognitive impairment after mild repetitive head injuries. The lack of common biomarkers suggests novel unknown underlying mechanisms of rmTBI.