Istradefylline protects from cisplatin-induced nephrotoxicity and peripheral neuropathy while preserving cisplatin antitumor effects

Cisplatin is a potent chemotherapeutic drug that is widely used in the treatment of various solid cancers. However, its clinical effectiveness is strongly limited by frequent severe adverse effects, in particular nephrotoxicity and chemotherapy-induced peripheral neuropathy. Thus, there is an urgent medical need to identify novel strategies that limit cisplatin-induced toxicity. In the present study, we show that the FDA-approved adenosine A2A receptor antagonist istradefylline (KW6002) protected from cisplatin-induced nephrotoxicity and neuropathic pain in mice with or without tumors. Moreover, we also demonstrate that the antitumoral properties of cisplatin were not altered by istradefylline in tumor-bearing mice and could even be potentiated. Altogether, our results support the use of istradefylline as a valuable preventive approach for the clinical management of patients undergoing cisplatin treatment

Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents

Opiates are essential for treating pain, but termination of opiate therapy can cause a debilitating withdrawal syndrome in chronic users. To alleviate or avoid the aversive symptoms of withdrawal, many of these individuals continue to use opiates. Withdrawal is therefore a key determinant of opiate use in dependent individuals, yet its underlying mechanisms are poorly understood and effective therapies are lacking. Here, we identify the pannexin-1 (Panx1) channel as a therapeutic target in opiate withdrawal. We show that withdrawal from morphine induces long-term synaptic facilitation in lamina I and II neurons within the rodent spinal dorsal horn, a principal site of action for opiate analgesia. Genetic ablation of Panx1 in microglia abolished the spinal synaptic facilitation and ameliorated the sequelae of morphine withdrawal. Panx1 is unique in its permeability to molecules up to 1 kDa in size and its release of ATP. We show that Panx1 activation drives ATP release from microglia during morphine withdrawal and that degrading endogenous spinal ATP by administering apyrase produces a reduction in withdrawal behaviors. Conversely, we found that pharmacological inhibition of ATP breakdown exacerbates withdrawal. Treatment with a Panx1-blocking peptide (10panx) or the clinically used broad-spectrum Panx1 blockers, mefloquine or probenecid, suppressed ATP release and reduced withdrawal severity. Our results demonstrate that Panx1-mediated ATP release from microglia is required for morphine withdrawal in rodents and that blocking Panx1 alleviates the severity of withdrawal without affecting opiate analgesia

Characterizing circadian behaviour in the BTBR mouse model

Circadian rhythms span across species and temporally co-ordinate behaviour and physiological processes to not only maintain a rhythm in the absence of cues but to also effectively coincide with external time giving cycles. A disruption in circadian rhythms causes a variety of psychological and physiological health impacts and can worsen already present disease states. Sleep and circadian issues are also comorbid with many disease and disorder states. Finding ways to alleviate the impact of circadian disruption is thus crucial. We characterized circadian behaviour in BTBR mice, that are used to model aspects of ASD. We found that BTBR mice differ drastically from C57BL/6J mice on many measures of circadian behaviour including, their free running period, their duration of activity, their total activity, their response to dark pulses in LL their entrainment patterns to shifted light dark cycle, their food anticipatory activity to schedules feeding and in the number of VIP and AVP cells in the SCN. Despite their short FRP BTBR mice entrained to ambient light cycles with stability and precision, a property that is not commonly observed. Additionally, they had more drastic changes in constant light conditions when compared to C57 controls. Despite this they maintained normal responses to light pulses, suggesting a conservation light input pathway, instead a possible dysregulation of arousal pathways, which aligns with what is known about BTBR physiology. We also found differences in VIP and AVP expressing cells in the BTBR SCN. Both these peptides have been implicated in the circadian entrainment to light cycle. Therefore, the BTBR mouse model provides not only the novel opportunity to study the mechanisms of circadian rhythms in a mouse with a drastically altered phenotype, but also can be used to study circadian rhythms when they are dysregulated. Finally, their precise entrainment might provide clues of how to better deal with circadian disruption and how to optimize entrainment to changing light cycles

Erratum: Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents.

Opiates are essential for treating pain, but termination of opiate therapy can cause a debilitating withdrawal syndrome in chronic users. To alleviate or avoid the aversive symptoms of withdrawal, many of these individuals continue to use opiates. Withdrawal is therefore a key determinant of opiate use in dependent individuals, yet its underlying mechanisms are poorly understood and effective therapies are lacking. Here, we identify the pannexin-1 (Panx1) channel as a therapeutic target in opiate withdrawal. We show that withdrawal from morphine induces long-term synaptic facilitation in lamina I and II neurons within the rodent spinal dorsal horn, a principal site of action for opiate analgesia. Genetic ablation of Panx1 in microglia abolished the spinal synaptic facilitation and ameliorated the sequelae of morphine withdrawal. Panx1 is unique in its permeability to molecules up to 1 kDa in size and its release of ATP. We show that Panx1 activation drives ATP release from microglia during morphine withdrawal and that degrading endogenous spinal ATP by administering apyrase produces a reduction in withdrawal behaviors. Conversely, we found that pharmacological inhibition of ATP breakdown exacerbates withdrawal. Treatment with a Panx1-blocking peptide (10panx) or the clinically used broad-spectrum Panx1 blockers, mefloquine or probenecid, suppressed ATP release and reduced withdrawal severity. Our results demonstrate that Panx1-mediated ATP release from microglia is required for morphine withdrawal in rodents and that blocking Panx1 alleviates the severity of withdrawal without affecting opiate analgesia