PALMITOYLETHANOLAMIDE, AN ENDOGENOUS PPAR-ALPHA AGONIST, MODULATES NEUROSTEROIDS DE NOVO SYNTHESIS

Palmitoylethanolamide (PEA), a member of fatty-acid ethanolamide family, is an endogenous neuromodulator with a broad spectrum of pharmacological properties, including analgesic (Calignano et al., 1998, 2001), anti-inflammatory (Costa et al., 2002; D’Agostino et al., 2007), anticonvulsant (Lambert et al., 2001) and antiproliferative (Di Marzo et al., 2001) effects. Less investigated are the functions of PEA in the central nervous system (CNS), where PEA is present in detectable levels (Cadas et al., 1997), showing diurnal variation (Rodriguez et al., 2006). Despite its molecular target remain debate, PEA failed to exert its analgesic and anti-inflammatory properties in mice lacking peroxisome proliferator-activated receptor alpha (PPAR-α) (LoVerme et al., 2005; D’Agostino et al., 2007). Although PPAR-α is a well characterized transcription factor (Lemberger et al., 1996), it seems to be pivotal for other effects not strictly related to its transcriptional activity, such as the effect on calcium-activated K+ channels, mediating rapid analgesia (Lo Verme et al., 2006). Likewise PEA, PPAR-α has been localized in discrete areas of the CNS with a peculiar distribution (Kainu et al., 1994; Moreno et al., 2004; Benani et al., 2004), although its role in these areas is unclear and poorly defined. In the last ten years it has emerged that neurosteroids are strongly involved in several physiological cognitive and emotive functions of the CNS (Jung-Testas and Baulieu, 1998). Neurosteroids are known to exert several rapid effects, including modulation of hypnosis, through activation of GABAA receptors, these studies have been mainly conducted with the action of pregnenolone-like neuroactive steroid (Mendelson et al., 1987), and metyrapone, a blocker of the enzyme 11β-hydroxylase, which is essential for the biosynthesis of corticosteroids (Burade et al., 1996). Keller et al. (2004) have shown that 5α-reduced neurosteroids act on GABAA, as well as peripheral benzodiazepine receptor (PBR), modulating the GABA-induced Cl- currents that result in neuron hyperpolarization. Among 5α-reduced neuroactive steroids, the 3α-hydroxy-5α-pregnan-20-one (allopregnanolone, ALLO) displays anxiolytic, sedative, analgesic and anaesthetic properties (Rupprecht et al., 2001), causing a great pharmacological interest. The main pharmacological properties above reported are shared with those of PEA. Particularly, it was previously reported that N-acylethanolamines of unsaturated fatty acid (N-linoleoyl-, N-oleoyl-) and of saturated fatty acid (PEA), significantly prolonged pentobarbital-induced hypnosis in mice (Watanabe et al., 1999). Here, we hypothesize that exogenous administration of PEA, through a PPAR-α-dependent mechanism, participates in neurosteroid formation increasing their levels and leading to a positive modulation of GABAA receptor. For this aim, we study the effect of PEA in vitro using C6 glioma cell line and primary murine astrocytes, which, as other glial cells and neurons, have the enzymatic machinery for de novo synthesis of neurosteroids and in vivo using pentobarbital induced LORR duration and EEG recordings in mouse. In particular, Fast Fourier Transformer (FFT) power spectral analysis was applied to reveal the time change of slow wave activity in the EEG, which would provide some quantitative measures of LORR EEG. The demonstration of the capacity of a neural centre to synthesize neurosteroids requires the localization in that centre of active forms of key steroidogenic enzymes, and local increase of neurosteroids. Therefore, we evaluated the ALLO content and the expression of StAR and P450scc, two proteins implicated in the early step of neurosteroidogenesis in mitochondrial fraction, supernatant and brainstem. As well known, this area serves integrative functions, including, pain sensitivity control, alertness, and consciousness, and shows appreciable and functional levels of PEA (Petrosino et al., 2007; Melis et al., 2008), as well as of PPAR-α (Moreno et al., 2004; Melis et al., 2008)

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Peripheral gating of pain signals by endogenous lipid mediators.

Primary sensory afferents and their neighboring host-defense cells are a rich source of lipid-derived mediators that contribute to the sensation of pain caused by tissue damage and inflammation. But an increasing number of lipid molecules have been shown to act in an opposite way, to suppress the inflammatory process, restore homeostasis in damaged tissues and attenuate pain sensitivity by regulating neural pathways that transmit nociceptive signals from the periphery of the body to the CNS. Here we review the molecular and cellular mechanisms that contribute to the modulatory actions of lipid mediators in peripheral nociceptive signaling

Peripheral gating of pain signals by endogenous lipid mediators.

Primary sensory afferents and their neighboring host-defense cells are a rich source of lipid-derived mediators that contribute to the sensation of pain caused by tissue damage and inflammation. But an increasing number of lipid molecules have been shown to act in an opposite way, to suppress the inflammatory process, restore homeostasis in damaged tissues and attenuate pain sensitivity by regulating neural pathways that transmit nociceptive signals from the periphery of the body to the CNS. Here we review the molecular and cellular mechanisms that contribute to the modulatory actions of lipid mediators in peripheral nociceptive signaling