Oral treatment with a brain-penetrant NLRP3 inhibitor has protective effects in preclinical models of Parkinson’s disease.

The sequelae of diabetes include microvascular complications such as diabetic kidney disease (DKD), which involves glucose-mediated renal injury associated with a disruption in mitochondrial metabolic agility, inflammation, and fibrosis. We explored the role of the innate immune complement component C5a, a potent mediator of inflammation, in the pathogenesis of DKD in clinical and experimental diabetes. Marked systemic elevation in C5a activity was demonstrated in patients with diabetes; conventional renoprotective agents did not therapeutically target this elevation. C5a and its receptor (C5aR1) were upregulated early in the disease process and prior to manifest kidney injury in several diverse rodent models of diabetes. Genetic deletion of C5aR1 in mice conferred protection against diabetes-induced renal injury. Transcriptomic profiling of kidney revealed diabetes-induced downregulation of pathways involved in mitochondrial fatty acid metabolism. Interrogation of the lipidomics signature revealed abnormal cardiolipin remodeling in diabetic kidneys, a cardinal sign of disrupted mitochondrial architecture and bioenergetics. In vivo delivery of an orally active inhibitor of C5aR1 (PMX53) reversed the phenotypic changes and normalized the renal mitochondrial fatty acid profile, cardiolipin remodeling, and citric acid cycle intermediates. In vitro exposure of human renal proximal tubular epithelial cells to C5a led to altered mitochondrial respiratory function and reactive oxygen species generation. These experiments provide evidence for a pivotal role of the C5a/C5aR1 axis in propagating renal injury in the development of DKD by disrupting mitochondrial agility, thereby establishing a new immunometabolic signaling pathway in DKD.

The cyclic hexapeptides PMX53 and PMX205 are potent noncompetitive inhibitors of complement C5a receptor 1 (C5aR1). They are widely utilized to study the role of C5aR1 in mouse models, including central nervous system (CNS) disease, and are dosed through a variety of routes of administration. However, a comprehensive pharmacokinetics analysis of these drugs has not been reported. In this study, the blood and CNS pharmacokinetics of PMX53 and PMX205 were performed in mice following intravenous, intraperitoneal, subcutaneous, and oral administration at identical doses. The absorption and distribution of both drugs were rapid and followed a two-compartment model with elimination half-lives of ∼20 min for both compounds. Urinary excretion was the major route of elimination following intravenous dosing with ∼50% of the drug excreted unchanged within the first 12 h. Oral bioavailability of PMX205 was higher than that of PMX53 (23% versus 9%), and PMX205 was also more efficient than PMX53 at entering the intact CNS. In comparison to other routes, subcutaneous administration of PMX205 resulted in high bioavailability (above 90%), as well as prolonged plasma and CNS exposure. Finally, repeated daily oral or subcutaneous administration of PMX205 demonstrated no accumulation of drug in blood, the brain, or the spinal cord, promoting its safety for chronic dosing. These results will be helpful in correlating the desired therapeutic effects of these C5aR1 antagonists with their pharmacokinetic profile. It also suggests that subcutaneous dosing of PMX205 may be an appropriate route of administration for future clinical testing in neurological disease.

Huntington's disease (HD) is an incurable neurodegenerative condition characterized by progressive motor and cognitive dysfunction, and depletion of neurons in the striatum. Recently, BACHD transgenic mice expressing the full-length human huntingtin gene have been generated, which recapitulate some of the motor and cognitive deficits seen in HD. In this study, we carried out a series of extensive behavioural and neuropathological tests on BACHD mice, to validate this mouse for preclinical research. Transgenic C57BL/6J BACHD and litter-matched wild-type mice were examined in a battery of motor and cognitive function tests at regular intervals up to 12 months of age. Brains from these mice were also analysed for signs of neurodegeneration and striatal and cortical volume sizes compared using anatomic 16.4T magnetic resonance imaging (MRI) brain scans. BACHD mice showed progressive motor impairments on rotarod and balance beam tests starting from 3 months of age, were hypoactive in the open field tests starting from 6 months of age, however, showed no alterations in gait and grip strength at any age. Surprisingly, despite these distinct motor deficits, no signs of neuronal loss, gliosis or blood–brain barrier degeneration were observed in the striatum of 12-month-old mice. MRI brain scans confirmed no reduction in striatal or cortical volumes at 12 months of age, and BACHD mice had a normal lifespan. These results demonstrate that classical Huntington's-like motor impairments seen in this transgenic model, do not occur due to degeneration of the striatum, and thus caution against the use of this model for preclinical studies into HD.