1 As pretreatment with intraperitoneal capsaicin CAP), an agonist of the vanilloid receptor known as VR1 or transient receptor potential channel-vanilloid receptor subtype 1 (TRPV-1), has been shown to block the first phase of lipopolysaccharide (LPS) fever in rats, this phase is thought to depend on the TRPV-1-bearing sensory nerve fibers originating in the abdominal cavity. However, our recent studies suggest that CAP blocks the first phase via a non-neural mechanism. In the present work, we studied whether this mechanism involves the TRPV-1. 2 Adult Long-Evans rats implanted with chronic jugular catheters were used. 3 Pretreatment with CAP (5 mg kg À1 , i.p.) 10 days before administration of LPS (10 mg kg À1 , i.v.) resulted in the loss of the entire first phase and a part of the second phase of LPS fever. 4 Pretreatment with the ultrapotent TRPV-1 agonist resiniferatoxin (RTX; 2, 20, or 200 mg kg À1 , i.p.) 10 days before administration of LPS had no effect on the first and second phases of LPS fever, but it exaggerated the third phase at the highest dose. The latter effect was presumably due to the known ability of high doses of TRPV-1 agonists to cause a loss of warm sensitivity, thus leading to uncontrolled, hyperpyretic responses. , i.p.) did not affect LPS fever, but blocked the immediate hypothermic response to acute administration of CAP. 6 It is concluded that LPS fever is initiated via a non-neural mechanism, which is CAP-sensitive but RTX-and CPZ-insensitive. The action of CAP on this mechanism is likely TRPV-1-independent. It is speculated that this mechanism may be the production of prostaglandin E 2 by macrophages in LPSprocessing organs.

The huntingtin N17 domain is a modulator of mutant huntingtin toxicity and is hypophosphorylated in Huntington's disease (HD). We conducted high-content analysis to find compounds that could restore N17 phosphorylation. One lead compound from this screen was N6-furfuryladenine (N6FFA). N6FFA was protective in HD model neurons, and N6FFA treatment of an HD mouse model corrects HD phenotypes and eliminates cortical mutant huntingtin inclusions. We show that N6FFA restores N17 phosphorylation levels by being salvaged to a triphosphate form by adenine phosphoribosyltransferase (APRT) and used as a phosphate donor by casein kinase 2 (CK2). N6FFA is a naturally occurring product of oxidative DNA damage. Phosphorylated huntingtin functionally redistributes and colocalizes with CK2, APRT, and N6FFA DNA adducts at sites of induced DNA damage. We present a model in which this natural product compound is salvaged to provide a triphosphate substrate to signal huntingtin phosphorylation via CK2 during low-ATP stress under conditions of DNA damage, with protective effects in HD model systems.

Obese (f/f) Koletsky rats lack the leptin receptor (LR), whereas their lean (F/?) counterparts bear a fully functional LR. By using f/f and F/? rats, we studied whether the LR is involved in lipopolysaccharide (LPS)‐induced fever and hypothermia. The body temperature responses to LPS (10 or 100 µg/kg iv) were measured in Koletsky rats exposed to a thermoneutral (28°C) or cool (22°C) environment. Rats of both genotypes responded to LPS with fever at 28°C and with dose‐dependent hypothermia at 22°C. The fever responses of the f/f and F/? rats were identical. The hypothermic response of the f/f rats was markedly prolonged compared with that of the F/? rats. The prolonged hypothermic response to LPS in the f/f rats was accompanied by enhanced NF‐κB signaling in the hypothalamus and an exaggerated rise in the plasma concentration of tumor necrosis factor (TNF)‐α. The f/f rats did not respond to LPS with an increase in the plasma concentration of corticosterone or adrenocorticotropic hormone, whereas their F/? counterparts did. The hypothermic response to TNF‐α (80 μg/kg iv) was markedly prolonged in the f/f rats. These data show that the LR is essential for the recovery from LPS hypothermia. LR‐dependent mechanisms of the recovery from LPS hypothermia include activation of the anti‐inflammatory hypothalamo‐pituitary‐adrenal axis, inhibition of both the production and hypothermic action of TNF‐α, and suppression of inflammatory (via NF‐κB) signaling in the hypothalamus.

Non-technical summary Systemic inflammation and related disorders, including sepsis, are leading causes of death in hospitalized patients. In most severe cases, systemic inflammation is accompanied by a drop in body temperature (hypothermia). We know that inflammation-associated hypothermia is a brain-mediated response, but mechanisms of this response are unknown. We administered a bacterial product (endotoxin) to rats to cause systemic inflammation and hypothermia. We then used a variety of pharmacological tools to probe whether three different receptors are involved in this hypothermia. We have found that one of the receptors studied, the so-called cannabinoid-1 (CB1) receptor, is crucial for the development of hypothermia. This is the same receptor that is responsible for many effects of marihuana (cannabis). We further show that hypothermia associated with inflammation depends on CB1 receptors located inside the brain. These novel findings suggest that brain CB1 receptors should be studied as potential therapeutic targets in systemic inflammation and sepsis.Abstract Hypothermia occurs in the most severe cases of systemic inflammation, but the mechanisms involved are poorly understood. This study evaluated whether the hypothermic response to bacterial lipopolysaccharide (LPS) is modulated by the endocannabinoid anandamide (AEA) and its receptors: cannabinoid-1 (CB1), cannabinoid-2 (CB2) and transient receptor potential vanilloid-1 (TRPV1). In rats exposed to an ambient temperature of 22• C, a moderate dose of LPS (25-100 μg kg −1 I.V.) induced a fall in body temperature with a nadir at ∼100 min postinjection. This response was not affected by desensitization of intra-abdominal TRPV1 receptors with resiniferatoxin (20 μg kg −1 I.P.), by systemic TRPV1 antagonism with capsazepine (40 mg kg −1 I.P.), or by systemic CB2 receptor antagonism with SR144528 (1.4 mg kgHowever, CB1 receptor antagonism by rimonabant (4.6 mg kg −1 I.P.) or SLV319 (15 mg kgblocked LPS hypothermia. The effect of rimonabant was further studied. Rimonabant blocked LPS hypothermia when administered I.C.V. at a dose (4.6 μg) that was too low to produce systemic effects. The blockade of LPS hypothermia by I.C.V. rimonabant was associated with suppression of the circulating level of tumour necrosis factor-α. In contrast to rimonabant, the I.C.V. administration of AEA (50 μg) enhanced LPS hypothermia. Importantly, I.C.V. AEA did not evoke hypothermia in rats not treated with LPS, thus indicating that AEA modulates LPS-activated pathways in the brain rather than thermoeffector pathways. In conclusion, the present study reveals a novel, critical role of brain CB1 receptors in LPS hypothermia. Brain CB1 receptors may constitute a new therapeutic target in systemic inflammation and sepsis.

Lipopolysaccharide (LPS)‐induced systemic inflammation is accompanied by either hypothermia (prevails when the ambient temperature (Ta) is subneutral) or fever (prevails when Ta is neutral or higher). Because platelet‐activating factor (PAF) is a proximal mediator of LPS inflammation, it should mediate both thermoregulatory responses to LPS. That PAF possesses hypothermic activity and mediates LPS‐induced hypothermia is known. We asked whether PAF possesses pyrogenic activity (Expt 1) and mediates LPS fever (Expt 2). The study was conducted in Long‐Evans rats implanted with jugular catheters. A complex with bovine serum albumin (BSA) was infused as a physiologically relevant form of PAF; free (aggregated) PAF was used as a control. In Expt 1, either form of PAF caused hypothermia when infused (83 pmol kg‐1 min‐1, 60 min, i.v.) at a subneutral Ta of 20 °C, but the response to the PAF‐BSA complex (−4.5 ± 0.5 °C, nadir) was ~4 times larger than that to free PAF. At a neutral Ta of 30 °C, both forms caused fever preceded by tail skin vasoconstriction, but the febrile response to PAF‐BSA (1.0 ± 0.1 °C, peak) was > 2 times higher than that to free PAF. Both the hypothermic (at 20 °C) and febrile (at 30 °C) responses to PAF‐BSA started when the total amount of PAF infused was extremely small, < 830 pmol kg‐1. In Expt 2 (conducted at 30 °C), the PAF receptor antagonist BN 52021 (29 µmol kg‐1, i.v.) had no thermal effect of itself. However, it strongly (~2 times) attenuated the febrile response to PAF (5 nmol kg‐1, i.v.), implying that this response involves the PAF receptor and is not due to a detergent‐like effect of PAF on cell membranes. BN 52021 (but not its vehicle) was similarly effective in attenuating LPS (10 µg kg‐1, i.v.) fever. It is concluded that PAF is a highly potent endogenous pyrogenic substance and a mediator of LPS fever.