Hibernation in Arctic ground squirrels (AGS), Spermophilus parryii, is characterized by a profound decrease in oxygen consumption and metabolic demand during torpor that is punctuated by periodic rewarming episodes, during which oxygen consumption increases dramatically. The extreme physiology of torpor or the surge in oxygen consumption during arousal may increase production of reactive oxygen species, making hibernation an injurious process for AGS. To determine if AGS tissues experience cellular stress during rewarming, we measured carbonyl proteins, lipid peroxide end products and percent oxidized glutathione in brown adipose tissue (BAT) and liver of torpid, hibernating (hAGS), late arousal (laAGS), and cold-adapted, euthermic AGS (eAGS). In BAT carbonyl proteins and lipid peroxide end products were higher in eAGS and laAGS than in hAGS. By contrast, in liver, no significant difference in carbonyl proteins was observed. In another group of animals, comparison of carbonyl proteins and percent oxidized glutathione in frontal cortex, liver, and BAT of eAGS and hAGS showed no evidence of oxidative stress associated with torpor. These results indicate that increased thermogenesis associated with arousal AGS results in tissue specific oxidative stress in BAT but not in liver. Moreover, torpor per se is largely devoid of oxidative stress, likely due to suppression of oxidative metabolism.

a b s t r a c tIntroduction: Depletion of neuronal glutathione may contribute to the pathogenesis of Parkinson's disease (PD). N-acetylcysteine (NAC) can restore neuronal glutathione levels, but it has not been established whether NAC can cross the bloodebrain barrier in humans. Methods: Twelve patients with PD were given oral NAC twice daily for 2 days. Three doses were compared: 7 mg/kg, 35 mg/kg, and 70 mg/kg. NAC, cysteine, and glutathione were measured in the cerebrospinal fluid (CSF) at baseline and 90 min after the last dose. Cognitive and motor functions were assessed pre-and post-NAC administration using the Montreal Cognitive Assessment (MoCA) and the Unified Parkinson's Disease Rating Scale part III motor subscore (UPDRS-III). Results: Oral NAC produced a dose-dependent increase in CSF NAC concentrations (p < 0.001), with the highest dose producing a CSF concentration of 9.26 ± 1.62 mM. There were no significant adverse events.NAC had no acute effect on motor or cognitive function. Conclusion: Orally administered NAC produces biologically relevant CSF NAC concentrations at doses that are well tolerated. The findings support the feasibility of NAC as a potential disease-modifying therapy for PD.

Summary It has been widely reported that β-amyloid peptide (Aβ) blocks long-term potentiation (LTP) of hippocampal synapses. Here we show evidence that Aβ more potently blocks the potentiation of excitatory post-synaptic potential (EPSP) -spike coupling (E-S potentiation). This occurs not by direct effect on excitatory synapses or postsynaptic neurons, but rather through a novel indirect mechanism: reduction of endocannabinoid-mediated peri-tetanic disinhibition. During high frequency (tetanic) stimulation, somatic synaptic inhibition is suppressed by endocannabinoids. We find that Aβ prevents this endocannabinoid-mediated disinhibition, thus leaving synaptic inhibition more intact during tetanic stimulation. This intact inhibition opposes the normal depolarization of hippocampal pyramidal neurons that occurs during tetanus, thus opposing the induction of synaptic plasticity. Thus, a novel pathway through which Aβ can act to modulate neural activity is identified, relevant to learning and memory and how it may mediate aspects of the cognitive decline seen in Alzheimer's disease.

Combination therapies targeting multiple recovery mechanisms have the potential for additive or synergistic effects, but experimental design and analyses of multimodal therapeutic trials are challenging. To address this problem, we developed a data-driven approach to integrate and analyze raw source data from separate pre-clinical studies and evaluated interactions between four treatments following traumatic brain injury. Histologic and behavioral outcomes were measured in 202 rats treated with combinations of an anti-inflammatory agent (minocycline), a neurotrophic agent (LM11A-31), and physical therapy consisting of assisted exercise with or without botulinum toxin-induced limb constraint. Data was curated and analyzed in a linked workflow involving non-linear principal component analysis followed by hypothesis testing with a linear mixed model. Results revealed significant benefits of the neurotrophic agent LM11A-31 on learning and memory outcomes after traumatic brain injury. In addition, modulations of LM11A-31 effects by co-administration of minocycline and by the type of physical therapy applied reached statistical significance. These results suggest a combinatorial effect of drug and physical therapy interventions that was not evident by univariate analysis. The study designs and analytic techniques applied here form a structured, unbiased, internally validated workflow that may be applied to other combinatorial studies, both in animals and humans.