IgE-mediated anaphylaxis is an acute life-threatening systemic reaction to allergens, including certain foods and venoms. Anaphylaxis is triggered when blood-borne allergens activate IgE-bound perivascular mast cells (MCs) throughout the body, causing an extensive systemic release of MC mediators. Through precipitating vasodilatation and vascular leakage, these mediators are believed to trigger a sharp drop in blood pressure in humans and in core body temperature in animals. We report that the IgE/MC-mediated drop in body temperature in mice associated with anaphylaxis also requires the body’s thermoregulatory neural circuit. This circuit is activated when granule-borne chymase from MCs is deposited on proximal TRPV1 ⁺ sensory neurons and stimulates them via protease-activated receptor-1. This triggers the activation of the body’s thermoregulatory neural network, which rapidly attenuates brown adipose tissue thermogenesis to cause hypothermia. Mice deficient in either chymase or TRPV1 exhibited limited IgE-mediated anaphylaxis, and, in wild-type mice, anaphylaxis could be recapitulated simply by systemically activating TRPV1 ⁺ sensory neurons. Thus, in addition to their well-known effects on the vasculature, MC products, especially chymase, promote IgE-mediated anaphylaxis by activating the thermoregulatory neural circuit.

Mn(III) ortho‐N‐alkyl‐ and N‐alkoxyalkyl porphyrins (MnPs) were initially developed as superoxide dismutase (SOD) mimics. These compounds were later shown to react with numerous reactive species (such as ONOO^-, H₂O₂, H₂S, CO₃^•-, ascorbate, and GSH). Moreover, the ability of MnPs to oxidatively modify activities of numerous proteins has emerged as their major mechanism of action both in normal and in cancer cells. Among those proteins are transcription factors (NF‐κB and Nrf2), mitogen‐activated protein kinases, MAPKs, antiapoptotic bcl‐2, and endogenous antioxidative defenses. The lead Mn porphyrins, namely, MnTE‐2‐PyP⁵⁺ (BMX‐010, AEOL10113), MnTnBuOE‐2‐PyP⁵⁺ (BMX‐001), and MnTnHex‐2‐PyP⁵⁺, were tested in numerous injuries of normal tissue and cellular and animal cancer models. The wealth of the data led to the progression of MnTnBuOE‐2‐PyP⁵⁺ into four Phase II clinical trials on glioma, head and neck cancer, anal cancer, and multiple brain metastases, while MnTE‐2‐PyP⁵⁺ is in Phase II clinical trial on atopic dermatitis and itch.

Risk for ischemic stroke has a strong genetic basis, but heritable factors also contribute to the extent of damage after a stroke has occurred. We previously identified a locus on distal mouse chromosome 7 that contributes over 50% of the variation in postischemic cerebral infarct volume observed between inbred strains. Here, we used ancestral haplotype analysis to fine-map this locus to 12 candidate genes. The gene encoding the IL-21 receptor (Il21r) showed a marked difference in strain-specific transcription levels and coding variants in neonatal and adult cortical tissue. Collateral vessel connections were moderately reduced in Il21r-deficient mice, and cerebral infarct volume increased 2.3-fold, suggesting that Il21r modulates both collateral vessel anatomy and innate neuroprotection. In brain slice explants, oxygen deprivation (OD) activated apoptotic pathways and increased neuronal cell death in IL-21 receptor–deficient (IL-21R–deficient) mice compared with control animals. We determined that the neuroprotective effects of IL-21R arose from signaling through JAK/STAT pathways and upregulation of caspase 3. Thus, natural genetic variation in murine Il21r influences neuronal cell viability after ischemia by modulating receptor function and downstream signal transduction. The identification of neuroprotective genes based on naturally occurring allelic variations has the potential to inform the development of drug targets for ischemic stroke treatment.

Experimental cardiac arrest (CA) in aging research is infrequently studied in part due to the limitation of animal models. We aimed to develop an easily performed mouse CA model to meet this need. A standard mouse KCl-induced CA model using chest compressions and intravenous epinephrine for resuscitation was modified by blood withdrawal prior to CA onset, so as to decrease the requisite KCl dose to induce CA by decreasing the circulating blood volume. The modification was then compared to the standard model in young adult mice subjected to 8 min CA. 22-month old mice were then subjected to 8 min CA, resuscitated, and compared to young adult mice. Post-CA functional recovery was evaluated by measuring spontaneous locomotor activity pre-injury, and on post-CA days 1, 2, and 3. Neurological score and brain histology were examined on day 3. Brain elF2α phosphorylation levels were measured at 1 h to verify tissue stress. Compared to the standard model, the modification decreased cardiopulmonary resuscitation duration and increased 3-day survival in young mice. For aged mice, survival was 100 % at 24 h and 54% at 72 h. Neurological deficit was present 3 days post-CA, although more severe versus young mice. Mild neuronal necrosis was present in the cortex and hippocampus. The modified model markedly induced elF2α phosphorylation in both age groups. This modified procedure makes the CA model feasible in aged mice and provides a practical platform for understanding injury mechanisms and developing therapeutics for elderly patients.

Cognitive dysfunction, a significant complication after subarachnoid hemorrhage (SAH), affects up to 60% of survivors. We hypothesized that oral simvastatin would improve vestibulomotor function and reduce cognitive dysfunction after experimental SAH in the rat, and explored the effects of simvastatin on vasospasm and regional cerebral blood flow (rCBF). In total 160 rats were enrolled. Randomization to simvastatin or vehicle occurred after double intracisternal blood injections. Effects of simvastatin 10 mg/kg/d (SV10), simvastatin 1.5 mg/kg/d, or vehicle on rotarod, Morris water maze, neuronal survival, cerebral arterial diameter, and rCBF were determined by a blinded observer (n=15/group). A dose dependent response to simvastatin was observed, with more rapid improvement in vestibulomotor function, less basilar arterial vasospasm, and improved cortical neuronal survival with SV10. However, rotarod performance in the SV10 group deteriorated after 1 week, which correlated with the increased plasma creatine kinase levels (r=−0.737; P=0.0002). Furthermore, when simvastatin was discontinued after 2 weeks, the usual treatment duration in SAH clinical trials, rotarod performance deteriorated acutely, rCBF returned to control values, and no long-term benefit was observed in terms of visual spatial memory. Continuing simvastatin 1.5 mg/kg/d for 5 weeks resulted in sustained improvement in rotarod performance, reduced escape latency (P=0.001), swimming distance (P=0.002), and swimming speed (P=0.03) versus vehicle (n=12/group). Our results indicate that long-term cognitive dysfunction after experimental SAH in the rat can be reduced by simvastatin. However, treatment had to be extended beyond 2 weeks, the traditional risk period for angiographic vasospasm, to improve long-term outcome.