Timing and Determinants of Postinjection Endophthalmitis after First-Time Anti-VEGF Administration: A Retrospective National Study in the American Academy of Ophthalmology IRIS® Registry (Intelligent

Alzheimer’s disease (AD) is a progressive neurological condition characterized pathologically by extracellular plaques consisting of β-amyloid (Aβ) and intracellular neurofibrillary tau-tangles, as well as neuronal loss and neuroinflammation. AD manifests significant cognitive decline, which primarily affects memory. Genetic mutations in genes encoding for amyloid precursor protein or presenilin are associated with early onset of AD, resulting in increased Aβ production and disrupted intracellular Ca homeostasis. This was the initial fundamental evidence supporting the two major hypotheses of AD pathogenesis: the amyloid cascade hypothesis [, ] and the Ca hypothesis [, ]. However, the channels involved in disrupted Ca homeostasis are not fully identified. One of the FDA-approved AD drugs, memantine, is a non-competitive antagonist to NMDA receptor/NR2B, and can only relieve symptoms in mild AD patients, implying that other types of Ca channels may also play a significant role in AD pathogenesis. Ca homeostasis is crucial for neuronal functions, which include development, survival, synaptic transmission, memory, and plasticity. Cellular Ca signals are regulated by the entry of Ca from the extracellular environment or the release of Ca from intracellular compartments through receptor/store-operated Ca entry (ROCE/SOCE) mechanisms [, ]. The transient receptor potential canonical (TRPC) family consists of seven members of the Ca-permeable nonselective cationic membrane channels within the TRP superfamily []. Other than TRPC2, which is encoded by a pseudogene in humans, the two TRPC1/4/5 and TRPC3/6/7 subfamily members are largely expressed in the central nervous system (CNS), especially in the developing cerebellum and hippocampus [–]. Given the increasingly recognized roles of the TRPC family members in multiple age-related diseases [], they have been widely considered as potential drug targets [], including for neurodegenerative diseases. However, their roles in chronic neurodegeneration are relatively understudied [] compared to those in acute CNS conditions which have been assessed experimentally in mouse models [–]. Among the TRPC family, TRPC6’s neuroprotective roles have been the most studied [–] including in several mouse models of familial AD. Overexpression of TRPC6 enhances spatial learning abilities in APP/PS1 mice partially via reducing the production and deposition of Aβ [], but also by Aβ-impaired Ca entry, as well as synaptic dendritic morphology and function in APP-KI models []. Moreover, reduced TRPC6 levels were detected in AD patients’ sera [, ]. Even though these two closely related subfamily members TRPC3 and TRPC6 were often reported as TRPC3/6 to play similar or overlapping roles from earlier research [], evidence is emerging more recently suggesting that TRPC3 may play a distinct role from TRPC6 in several experimental settings. For example, they display opposite expressional changes (e.g., upregulated TRPC3 and downregulated TRPC6) in rat hippocampus after seizure [, ], consistent with the originally identified pivotal roles of TRPC3 channels in the maintenance of cell excitability and induction of membrane depolarization [, ]. Of note, overactivated TRPC3 channels were also reported to cause maldeveloped cerebellar Purkinje neurons, underlying the ataxia phenotype in the moonwalk mice [, ]. Furthermore, overactivated TRPC3 channels negatively regulated hippocampal excitability via modulating the Ca-dependent afterhyperpolarization []. Altogether, we speculated that TRPC3 plays a significant role in AD pathogenesis as in many other age-related diseases []. Although a pyrazole-based compound (Pyr3) is widely regarded as a TRPC3-selective antagonist [], its poor stability in blood limits its use in in vivo studies. Therefore, we developed a pharmacological TRPC3 selective antagonist compound with more feasible CNS permeability and stability [] to investigate the potentially important role(s) of aberrant TRPC3 functions in AD pathogenesis in both in vitro and in vivo experiments.