Pterygopalatine Ganglion Cell Death as an Underrecognized Mechanism in Dry Eye Syndrome: A Hypothesis with Special Attention to Diabetic Etiology.

PURPOSE: To propose that progressive neuronal and satellite glial cell death within the pterygopalatine ganglion (PPG) is an underrecognized upstream mechanism in chronic aqueous-deficient dry eye, with particular relevance to diabetes mellitus, and to examine whether this ganglionic lesion also unifies broader secretory and cerebrovascular abnormalities into a single "diabetic secretory denervation syndrome". METHODS: A narrative, hypothesis-driven synthesis was performed across ocular surface disease, autonomic neuroscience, diabetic neuropathy, regulated cell death, surgical denervation models, and cerebrovascular physiology. PubMed was searched using both "pterygopalatine ganglion" and "sphenopalatine ganglion" as synonyms, combined with terms for cell death, diabetes, vidian neurectomy, and cerebrovascular function. Reference lists were hand-searched. RESULTS: The PPG is the sole parasympathetic relay for lacrimal, nasal, palatal, and conjunctival secretion, and a major source of vasodilator drive to the anterior cerebral circulation. Surgical interruption of this pathway reliably causes aqueous-deficient dry eye. In streptozotocin-induced diabetic rats, nitrergic PPG neurons undergo TUNEL-confirmed apoptosis during an irreversible second phase of diabetic nitrergic neuropathy, driven by the synergistic action of advanced glycation end products and endogenous nitric oxide through a caspase-3-dependent mechanism. Additional cell-death modalities (necroptosis, pyroptosis, ferroptosis, and satellite glial cell apoptosis) are predicted by analogy with other autonomic ganglia under equivalent metabolic stress. Its degeneration is therefore predicted to cause coordinated multi-territory secretory failure rather than isolated dry eye. CONCLUSION: PPG neurodegeneration has been directly demonstrated in the diabetic rodent ganglion and mechanistically anchored in AGE-RAGE (advanced glycation end products and their receptor, RAGE)-mediated apoptosis. Extending this experimentally grounded finding, we hypothesise that these deficits (diabetic dry eye, impaired nasal mucociliary clearance, palatine xerostomia, goblet cell depletion, and reduced cerebral perfusion) may share a common upstream ganglionic lesion, a unifying proposal that remains to be tested directly. The hypothesis generates testable predictions and reframes therapy toward neuroprotection of the PPG.