Objective Post-cardiac arrest therapeutic hypothermia (TH) improves outcomes in comatose cardiac arrest survivors. This study tests the hypothesis that the efficacy of post-cardiac arrest TH is dependent on the onset and duration of therapy. Design Prospective randomized laboratory investigation Setting University research laboratory Subjects 268 male Long Evans rats Interventions Post-cardiac arrest therapeutic hypothermia Measurements and Main Results Adult male Long Evans rats that achieved return of spontaneous circulation (ROSC) after a 10-min asphyxial cardiac arrest were block randomized to normothermia (37±1°C) or TH (33±1°C) initiated 0, 1, 4, or 8 hrs after ROSC and maintained for 24 or 48 hrs. TH initiated 0, 1, 4, and 8 hours after ROSC resulted in 7-day survival rates of 45%*, 36%*, 36%*, and 14% respectively compared to 17% for normothermic controls, and survival with good neurologic function rates of 24%*, 24%*, 19%*, and 0% respectively compared to 2% for normothermic controls (*p<0.05 vs. normothermia). These outcomes were not different when TH was maintained for 24 vs. 48 hours. In contrast, hippocampal CA1 pyramidal neuron counts were 53±27%*, 53±19%*, 51±24%*, and 65±16%* of normal respectively when TH initiated 0, 1, 4, or 8 hrs after ROSC compared to 9% in normothermic controls (*p<0.01 vs. normothermia). Furthermore, surviving neuron counts were greater when TH was maintained for 48 hrs compared to 24 hrs (68%±15%* vs. 42%±22%, *p<0.0001) Conclusions In this study, post-cardiac arrest TH resulted in comparable improvement of survival and survival with good neurologic function when initiated within 4-hours after ROSC. However, histological assessment of neuronal survival revealed a potentially broader therapeutic window and greater neuroprotection when TH was maintained for 48 vs. 24 hours.

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LSD produced its enhancement of Pavlovian conditioning through an effect on 5-HT(2A) receptors located in the dorsal hippocampus. The slight, short-lived enhancement of learning produced by LSD appears to be due to the development of desensitization of the 5-HT(2A) receptor within the hippocampus as a result of repeated administration of its agonist (LSD).

Traumatic axonal injury is characterized by early cytoskeletal proteolysis and disruption of axonal transport. Calpain inhibition has been shown to protect axons in rodent models of traumatic brain injury. However, in these models, both white and gray matter are injured, making it difficult to determine if calpain inhibitors are directly protecting injured axons. To address this issue, we used our rat optic nerve stretch model to test the hypothesis that early calpain inhibition directly protects central nervous system (CNS) axons following stretch injury. Rats were given an intravenous bolus of the calpain inhibitor MDL-28170 (30 mg/kg) 30 min prior to unilateral optic nerve stretch, followed by a 15 mg/kg/h intravenous infusion over the next 2.5 h. Immunohistochemical analysis of optic nerves 30 min after stretch injury revealed variable increases of calpaincleaved a-spectrin that appeared less evident in stretched nerves from drug-treated rats, although this difference was not statistically significant. Retrograde axonal transport measured by Fluorogold Ò labeling of retinal ganglion cells was significantly impaired after stretch injury. However, there was no difference in the number of Fluorogold-labeled cells in the vehicle vs. drug treatment groups. These results suggest that early short-duration calpain inhibitor therapy with MDL-28170 is not an effective strategy to prevent disruption of axonal transport following isolated axonal stretch injury in the CNS.

The calpain family of cysteine proteases has a well-established causal role in neuronal cell death following acute brain injury. However, the relative contribution of calpain isoforms has not been determined in in vivo models. Identification of the calpain isoform responsible for neuronal injury is particularly important given the differential role of calpain isoforms in normal physiology. This study evaluates the role of m-calpain and μ-calpain in an in vivo model of global brain ischemia. Adeno-associated viral vectors expressing short hairpin RNAs targeting the catalytic subunits of μ- or m-calpain were used to knockdown expression of the targeted isoforms in adult rat hippocampal CA1 pyramidal neurons. Knockdown of μ-calpain, but not m-calpain, prevented calpain activity 72 hours after 6-minute transient forebrain ischemia, increased long-term survival and protected hippocampal electrophysiological function. These findings represent the first in vivo evidence that reducing expression of an individual calpain isoform can decrease post-ischemic neuronal death and preserve hippocampal function.

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