Glaucoma is a group of optic neuropathies characterised by the degeneration of retinal ganglion cells, resulting in damage to the optic nerve head (ONH) and loss of vision in one or both eyes. Increased intraocular pressure (IOP) is one of the major aetiological risk factors in glaucoma, and is currently the only modifiable risk factor. However, 30–40% of glaucoma patients do not present with elevated IOP and still proceed to lose vision. The pathophysiology of glaucoma is therefore not completely understood, and there is a need for the development of IOP-independent neuroprotective therapies to preserve vision. Neuroinflammation has been shown to play a key role in glaucoma and, specifically, the NLRP3 inflammasome, a key driver of inflammation, has recently been implicated. The NLRP3 inflammasome is expressed in the eye and its activation is reported in pre-clinical studies of glaucoma. Activation of the NLRP3 inflammasome results in IL-1β processing. This pro inflammatory cytokine is elevated in the blood of glaucoma patients and is believed to drive neurotoxic inflammation, resulting in axon degeneration and the death of retinal ganglion cells (RGCs). This review discusses glaucoma as an inflammatory disease and evaluates targeting the NLRP3 inflammasome as a therapeutic strategy. A hypothetical mechanism for the action of the NLRP3 inflammasome in glaucoma is presented.

Depression is characterised by a low mood, loss of interest or pleasure, pessimism, impaired concentration, decreased energy, and fatigue. A strong relationship between inflammatory processes and the pathophysiology of depression had been identified. Studies have suggested that the NLRP3 inflammasome is a key contributor to the pathogenesis of depression. This systematic review aimed to synthesise evidence from animal models of depression to evaluate both priming and activation of the inflammasome, with a specific focus on clarifying the role in depressive pathology. PubMed, Scopus, Web of Science, EMBASE and Medline were searched up until November 2024. Studies involving animal models of depression, measuring NLRP3 inflammasome components (NLRP3, ASC, Caspase-1 and IL-1β) were eligible for inclusion. Risk of bias was assessed using SYRCLEs Risk of Bias tool, and random-effects meta-analysis was conducted for each inflammasome component using RevMan. A total of 3345 studies were identified, with 23 accepted after full text screening, and 16 included in the meta-analysis. Across 170 animals (85 depression model, 85 controls), protein and mRNA levels of NLRP3, ASC, Caspase-1, and IL-1β were significantly upregulated in depression models compared to controls. Analysed brain regions included the hippocampus and prefrontal cortex. Moderate heterogeneity was observed between studies (I² = 0-68 %). This systematic review and meta-analysis demonstrates consistent upregulation of NLRP3 inflammasome components in animal models of depression, therefore suggesting an association with depression. Further research should investigate the therapeutic potential of targeting the NLRP3 inflammasome to reduce neuroinflammation and alleviate depression symptoms in both animal and human studies.

Background: Various studies have reported altered expression of metalloproteinases in Alzheimer's disease (AD); however, expression profiles of each metalloproteinase during cognitive decline have not yet been fully characterized. Objective: The purpose of this systematic review was to generate a comprehensive overview of metalloproteinases and their cognate inhibitors expression in AD and mild cognitive impairment (MCI), across sample matrices, to determine whether metalloproteinases are dysregulated in AD and may have predictive power in individuals with cognitive decline. Methods: An electronic literature search was conducted in PubMed, EMBASE, Scopus and MEDLINE from inception to December 2024. Sixty-one publications reporting metalloproteinase and inhibitor levels in 8576 patients with AD or MCI, and 7333 controls were included in the systematic review, twenty-one of which were extracted for meta-analysis. Standardized mean difference (SMD) was used to illustrate comparisons, and the Newcastle-Ottawa scale to assess bias. Results: Higher levels of cerebrospinal fluid (CSF) tissue inhibitor of metalloproteinase-2 (TIMP-2; p = 0.0003) were observed in the AD group and in patients with MCI ( p = 0.0009) compared to cognitively healthy controls. Following sensitivity analysis, significantly higher levels of CSF MMP-10 ( p = 0.0005) and lower plasma TIMP-2 ( p = 0.004) were also noted in patients with AD. TIMP-3, across all sample matrices, was decreased in patients with MCI versus controls ( p = 0.01). Conclusions: Significantly altered levels of metalloproteinases and their inhibitors were verified between patients with AD and MCI, representing potential biomarkers and prospective therapeutic targets for cognitive decline. This study was registered with PROSPERO, CRD42024628202.