Comparison of Femoral Nerve Catheter, Adductor Canal Catheter, and Periarticular Liposomal Bupivacaine Infiltration for Postoperative Analgesia After Primary Total Knee Arthroplasty.

BACKGROUND: Peripheral nerve catheters are used to provide analgesia after total knee arthroplasty (TKA) and have been shown to decrease pain and opioid use, to facilitate participation with physical therapy (PT), and to hasten discharge. More recently, pericapsular infiltration using liposomal bupivacaine (LB) has been employed as an alternative analgesic approach. METHODS: This retrospective study compared outcomes for three analgesic approaches: femoral nerve catheter (FNC), adductor canal catheter (ACC), and intraoperative LB infiltration. The primary outcome was numeric rating scale (NRS) pain scores at 24 hours. Secondary outcomes included pain scores at 12, 36, and 48 hours, time-to-first opioid, cumulative opioid use, distance walked, and time-to-discharge. RESULTS: Pain scores at 24 hours were significantly lower in both the ACC and FNC cohorts when compared to the LB cohort (3.1 versus 4.6 [P = .017] and 2.4 versus 4.6 [P < .0001]). The ACC and FNC groups did not differ significantly at that timepoint (P = .27). Similar comparisons were found at 12 and 36 hours, while at 48 hours the FNC group was superior. Time to first opioid and opioid consumption favored the ACC and FNC groups. Walking distance favored the ACC group. Both the ACC and LB groups had a faster time-to-discharge than the FNC group. CONCLUSION: Both ACCs and FNCs provided superior analgesia at 24 hours compared to LB, while being equivalent to each other. Pain scores at 12 hours and 36 hours as well as opioid consumption through 48 hours mirrored this finding. Although various differences were found between groups in terms of time-to-first analgesic, walking distance and time-to-discharge, the ACC approach appeared to optimally balance analgesia, ambulation, and time-to-discharge.

Restored glial glutamate transporter EAAT2 function as a potential therapeutic approach for Alzheimer's disease.

Glutamatergic systems play a critical role in cognitive functions and are known to be defective in Alzheimer's disease (AD) patients. Previous literature has indicated that glial glutamate transporter EAAT2 plays an essential role in cognitive functions and that loss of EAAT2 protein is a common phenomenon observed in AD patients and animal models. In the current study, we investigated whether restored EAAT2 protein and function could benefit cognitive functions and pathology in APPSw,Ind mice, an animal model of AD. A transgenic mouse approach via crossing EAAT2 transgenic mice with APPSw,Ind. mice and a pharmacological approach using a novel EAAT2 translational activator, LDN/OSU-0212320, were conducted. Findings from both approaches demonstrated that restored EAAT2 protein function significantly improved cognitive functions, restored synaptic integrity, and reduced amyloid plaques. Importantly, the observed benefits were sustained one month after compound treatment cessation, suggesting that EAAT2 is a potential disease modifier with therapeutic potential for AD.

Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection.

Glial glutamate transporter EAAT2 plays a major role in glutamate clearance in synaptic clefts. Several lines of evidence indicate that strategies designed to increase EAAT2 expression have potential for preventing excitotoxicity, which contributes to neuronal injury and death in neurodegenerative diseases. We previously discovered several classes of compounds that can increase EAAT2 expression through translational activation. Here, we present efficacy studies of the compound LDN/OSU-0212320, which is a pyridazine derivative from one of our lead series. In a murine model, LDN/OSU-0212320 had good potency, adequate pharmacokinetic properties, no observed toxicity at the doses examined, and low side effect/toxicity potential. Additionally, LDN/OSU-0212320 protected cultured neurons from glutamate-mediated excitotoxic injury and death via EAAT2 activation. Importantly, LDN/OSU-0212320 markedly delayed motor function decline and extended lifespan in an animal model of amyotrophic lateral sclerosis (ALS). We also found that LDN/OSU-0212320 substantially reduced mortality, neuronal death, and spontaneous recurrent seizures in a pilocarpine-induced temporal lobe epilepsy model. Moreover, our study demonstrated that LDN/OSU-0212320 treatment results in activation of PKC and subsequent Y-box-binding protein 1 (YB-1) activation, which regulates activation of EAAT2 translation. Our data indicate that the use of small molecules to enhance EAAT2 translation may be a therapeutic strategy for the treatment of neurodegenerative diseases.

Increased glial glutamate transporter EAAT2 expression reduces epileptogenic processes following pilocarpine-induced status epilepticus.

Several lines of evidence indicate that glutamate plays a crucial role in the initiation of seizures and their propagation; abnormal glutamate release causes synchronous firing of large populations of neurons, leading to seizures. In the present study, we investigated whether enhanced glutamate uptake by increased glial glutamate transporter EAAT2, the major glutamate transporter, could prevent seizure activity and reduce epileptogenic processes. EAAT2 transgenic mice, which have a 1.5-2 fold increase in EAAT2 protein levels as compared to their non-transgenic counterparts, were tested in a pilocarpine-induced status epilepticus (SE) model. Several striking phenomena were observed in EAAT2 transgenic mice compared with their non-transgenic littermates. First, the post-SE mortality rate and chronic seizure frequency were significantly decreased. Second, neuronal degeneration in hippocampal subfields after SE were significantly reduced. Third, the SE-induced neurogenesis and mossy fiber sprouting were significantly decreased. The severity of cell loss in epileptic mice was positively correlated with that of mossy fiber sprouting and chronic seizure frequency. Our results suggest that increased EAAT2 expression can protect mice against SE-induced death, neuropathological changes, and chronic seizure development. This study suggests that enhancing EAAT2 protein expression is a potential therapeutic approach.