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PSD-95 inhibitors have been shown to be neuroprotective in stroke, but have only to a very limited extent been evaluated in the treatment of traumatic brain injury ( TBI) that has pathophysiological mechanisms in common with stroke. The aims of the current study were to assess the effects of a novel dimeric inhibitor of PSD-95, UCCB01-147, on histopathology and long-term cognitive outcome after controlled cortical impact ( CCI) in rats. As excitotoxic cell death is thought to be a prominent part of the pathophysiology of TBI, we also investigated the neuroprotective effects of UCCB01-147 and related compounds on NMDA-induced cell death in cultured cortical neurons. Anesthetized rats were given a CCI or sham injury, and were randomized to receive an injection of either UCCB01-147 (10 mg/kg), the non-competitive NMDAR-receptor antagonist MK-801 (1 mg/kg) or saline immediately after injury. At 2 and 4 weeks post-trauma, spatial learning and memory were assessed in a water maze, and at 3 months, brains were removed for estimation of lesion volumes. Overall, neither treatment with UCCB01-147 nor MK-801 resulted in significant improvements of cognition and histopathology after CCI. Although MK-801 provided robust neuroprotection against NMDA-induced toxicity in cultured cortical neurons, UCCB01-147 failed to reduce cell death and became neurotoxic at high doses. The data suggest potential differential effects of PSD-95 inhibition in stroke and TBI that should be investigated further in future studies taking important experimental factors such as timing of treatment, dosage, and anesthesia into consideration. [ABSTRACT FROM AUTHOR]

Purpose: To i) evaluate the effect of a restraint procedure (7 days, 2 h/day) on place learning after fimbria-fornix transection (FF), ii) investigate effects of early vs. late administration of restraint, and iii) establish effects of the restraint procedure on expression of brain derived neurotrophic factor (BDNF) in prefrontal cortex and hippocampus. Methods: Fifty rats subjected to FF or sham surgery and divided into groups exposed to restraint immediately (early restraint) or 21 days (late restraint) after surgery were trained to acquire an allocentric place learning task. In parallel, 29 animals were subjected to FF or sham surgery and an identical restraint procedure in order to measure concentrations of BDNF and corticosterone. Results: The performance of the sham operated rats was positively affected by the late restraint. In FF-lesioned animals, the late restraint significantly improved task performance compared to the lesioned group with no restraint, while the early restraint was associated with a negative impact on task acquisition. Biochemical analysis after restraint procedure revealed a lesion-induced upregulation of BDNF in FF animals. Conclusions: The improved task performance of lesioned animals suggests a therapeutic effect of this manipulation, independent of BDNF. This effect is sensitive to the temporal administration of treatment. [ABSTRACT FROM AUTHOR]

Studies addressing cerebral functional localization face methodological and theoretical problems. Lesion experiments expect that when a functionally specialized structure is missing, its function can be deduced from the resulting impairments. Mostly, however, initial impairments are partially or fully eliminated through functional recovery. Apparently, such a recovery contradicts the notion of functional localization. In order to understand the mechanisms of recovery, improved methodology and a new theoretical framework are required. Insights into the mechanisms of recovery can be achieved by using “challenge” techniques, where functionally recovered individuals are exposed to organic and behavioral challenges, e.g. pharmacological manipulations or additional lesions, as well as modified test situations. Using such methods, a number of principles of functional recovery have emerged. We evaluate some of the available theories of post-traumatic recovery against these principles and find that none of them can account for the principles. Finally, we present a new conceptual framework – the Reorganization of Elementary Functions (REF) model. This model reconceptualizes the term “function”, suggests mechanisms of post-traumatic reorganizations, and resolves the contradiction between localization and functional recovery. [ABSTRACT FROM AUTHOR]