A next generation peripherally restricted Cavα2δ-1 ligand with inhibitory action on Cav2.2 channels and utility in neuropathic pain.

The Voltage-Gated Calcium Channel (VGCC) auxiliary subunit Cavα2δ-1 (CACNA2D1) is the target/receptor of gabapentinoids which are known therapeutics in epilepsy and neuropathic pain. Following damage to the peripheral sensory nervous system, Cavα2δ-1 is upregulated in dorsal root ganglion (DRG) neurons in several animal models of chronic neuropathic pain. Gabapentinoids, such as gabapentin and pregabalin, engage with Cavα2δ-1 via binding an arginine residue (R241) within an RRR motif located at the N-terminus of human Cavα2δ-1. A novel, next generation gabapentinoid, engineered not to penetrate the brain, was able to generate a strong analgesic response in Chronic Constriction Injury animal model of chronic neuropathic pain and showed binding specificity for Cavα2δ-1 versus the Cavα2δ-2 subunit. This novel non-brain penetrant gabapentinoid, binds to R241 and a novel binding site on Cavα2δ-1, which is located within the VGCC_α2 domain, identified as a lysine residue within an IKAK amino acid motif (K634). The overall whole cell current amplitudes were diminished by the compound, with these inhibitory effects being diminished in R241A mutant Cavα2δ-1 subunits. The functional effects occurred at lower concentrations than those needed for inhibition by gabapentin or pregabalin, which apparently bound the Cavα2δ-1 subunit only on the R241 and not on the K634 residue. Our work sets the stage for the identification and characterisation of novel compounds with therapeutic properties in neuropathic pain and possibly in other disorders and conditions which require engagement of the Cavα2δ-1 target.

The effect of activated carbon addition on membrane bioreactor processes for wastewater treatment and reclamation - A critical review.

This review concentrates on the effect of activated carbon (AC) addition to membrane bioreactors (MBRs) treating wastewaters. Use of AC-assisted MBRs combines adsorption, biodegradation and membrane filtration. This can lead to advanced removal of recalcitrant pollutants and mitigation of membrane fouling. The relative contribution of adsorption and biodegradation to overall removal achieved by an AC-assisted MBR process can vary, and "biological AC" may not fully develop due to competition of target pollutants with bulk organics in wastewater. Thus periodic replenishment of spent AC is necessary. Sludge retention time (SRT) governs the frequency of spent AC withdrawal and addition of fresh AC, and is an important parameter that significantly influences the performance of AC-assisted MBRs. Of utmost importance is AC dosage because AC overdose may aggravate membrane fouling, increase sludge viscosity, impair mass transfer and reduce sludge dewaterability.