Effects of Dimeric PSD-95 Inhibition on Excitotoxic Cell Death and Outcome After Controlled Cortical Impact in Rats.

Therapeutic effects of PSD-95 inhibition have been demonstrated in numerous studies of stroke; however only few studies have assessed the effects of PSD-95 inhibitors in traumatic brain injury (TBI). As the pathophysiology of TBI partially overlaps with that of stroke, PSD-95 inhibition may also be an effective therapeutic strategy in TBI. The objectives of the present study were to assess the effects of a dimeric inhibitor of PSD-95, UCCB01-144, on excitotoxic cell death in vitro and outcome after experimental TBI in rats in vivo. In addition, the pharmacokinetic parameters of UCCB01-144 were investigated in order to assess uptake of the drug into the central nervous system of rats. After a controlled cortical impact rats were randomized to receive a single injection of either saline or two different doses of UCCB01-144 (10 or 20 mg/kg IV) immediately after injury. Spatial learning and memory were assessed in a water maze at 2 weeks post-trauma, and at 4 weeks lesion volumes were estimated. Overall, UCCB01-144 did not protect against NMDA-toxicity in neuronal cultures or experimental TBI in rats. Important factors that should be investigated further in future studies assessing the effects of PSD-95 inhibitors in TBI are discussed.

Effects of different delayed exercise regimens on cognitive performance in fimbria­fornix transected rats.

Studies have shown that exercise can positively influence cognitive performance after brain injury. This study investigated the effects of different exercise regimens on allocentric place learning after fimbria­fornix (FF) transection. One hundred and sixteen pre­shaped rats were subjected either to a mechanical transection of the FF or control sham surgery and divided into following groups: i) no exercise (NE), ii) voluntary exercise in a running wheel (RW), iii) forced swimming exercise administered as interval training of short (3x5 min) duration (FS­SI), iv) forced swimming exercise administered as interval training of long (3x15 min) duration (FS­LI), v) forced swimming exercise administered as one session of short (5 min) duration (FS­SS), and vi) forced swimming exercise administered as one session of long (15 min) duration (FS­LS). The exercise was initiated 21 days post­surgery. Subsequently, all animals were administered 28 acquisition sessions in an 8­arm radial maze. Both sham operated and lesioned animals showed a significant learning response, however, the lesion induced a marked and lasting impairment, which was not alleviated neither by voluntary nor forced (spaced or one­session only) exercise regimens. Exercise regimens had no effect on the place learning of control sham animals. We conclude that the lesion location as well as factors related to the exercise­ and cognitive testing protocols can profoundly influence the potential of exercise as a general recovery­promoting method.

Delayed voluntary exercise does not enhance cognitive performance after hippocampal injury: an investigation of differentially distributed exercise protocols.

Voluntary exercise has previously been shown to enhance cognitive recovery after acquired brain injury (ABI). The present study evaluated effects of two differentially distributed protocols of delayed, voluntary exercise on cognitive recovery using an allocentric place learning task in an 8-arm radial maze. Fifty-four Wistar rats were subjected to either bilateral transection of the fimbria-fornix (FF) or to sham surgery. Twenty-one days postinjury, the animals started exercising in running wheels either for 14 consecutive days (FF/exercise daily [ExD], sham/ExD) or every other day for 14 days (FF/exercise every second day [ExS], sham/ExS). Additional groups were given no exercise treatment (FF/not exercise [NE], sham/NE). Regardless of how exercise was distributed, we found no cognitively enhancing effects of exercise in the brain injured animals. Design and protocol factors possibly affecting the efficacy of post-ABI exercise are discussed.

Exercise-induced improvement in cognitive performance after fimbria-fornix transection depends on the timing of exercise administration.

BACKGROUND: Exercise after brain injury holds major therapeutic potentials, but it is still uncertain whether such an intervention should take place during the critical time window of intrinsic repair mechanisms. OBJECTIVE: To assess the effects of acute or delayed voluntary exercise in running wheels on post-injury allocentric place learning in an 8-arm radial maze. METHODS: Forty-eight pre-shaped male rats underwent fimbria-fornix transection (FF) or control surgery (Sham). The animals were divided into six groups: FF group with no access to exercise (FF/NE); FF group starting exercise 1day post-surgery (FF/E+1); FF group starting exercise 8days post-surgery (FF/E+8); FF group starting exercise 21days post-surgery (FF/E+21); Sham group with no access to exercise (Sham/NE), and Sham group starting exercise 1day post-surgery (Sham/E+1). After 7days of exercise 6h/day, all animals underwent 28 place learning acquisition sessions. RESULTS: The FF/E+21 group showed an enhanced acquisition of the task compared to FF/NE. The FF/E+1 and FF/E+8 groups also showed an enhanced task acquisition relative to FF/NE, however with a slower acquisition than the FF/E+21 group. CONCLUSION: The data underscores the link between exercise and functional recovery after brain injury and emphasizes the importance of optimal timing of this intervention.

Delayed restraint procedure enhances cognitive recovery of spatial function after fimbria-fornix transection.

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.