Hypothesis paperCells Tissues Organs · 2026Subscription-access publication

Pterygopalatine ganglion cell death as an underrecognized mechanism in dry eye syndrome

A hypothesis-driven anatomical and mechanistic synthesis proposing that diabetic injury to the pterygopalatine ganglion (PPG) may be an upstream cause of aqueous-deficient dry eye and a broader multi-territory secretory denervation syndrome.

Mugurel Constantin Rusu · Diana Alexandra Bănică · Alexandra Diana Vrapciu

Explore the evidence ↓PubMed ↗Publisher ↗

The central hypothesis

Chronic metabolic injury causes progressive loss of PPG neurons and satellite glial cells. Once functional reserve falls below a threshold, parasympathetic secretomotor output becomes insufficient for tear production and other PPG-dependent secretory territories.

Direct experimental anchorMechanistic extensionsTestable clinical predictions

What makes this different

The model shifts the focus from the lacrimal gland alone to an upstream autonomic relay. It links dry eye, nasal mucosal dysfunction, palatal secretion, conjunctival goblet-cell changes, and possibly cerebral perfusion through one anatomical lesion.

Graphical abstract of the diabetic secretory denervation syndrome

Graphical abstract supplied by the authors: upstream diabetic injury → PPG cell death → downstream secretory and vascular failure.

01 · Evidence architecture

Established, supported, and predicted are kept separate

The microsite makes the evidentiary status explicit. Diabetic nitrergic apoptosis in the PPG is directly demonstrated in rodents; other regulated cell-death modalities, satellite glial death, and the unified secretory syndrome remain mechanistic predictions or extrapolations.

Established in PPG

TUNEL-positive apoptosis of nNOS-positive PPG neurons in streptozotocin-diabetic rats; AGE/RAGE, endogenous NO, oxidative stress, and caspase-3 are mechanistically implicated.

Supported by pathway evidence

Loss of parasympathetic input reduces tearing; PPG injury or denervation can produce dry eye; sympathetic withdrawal remodels the PPG nitrergic phenotype.

Predicted / not yet directly shown in PPG

Necroptosis, pyroptosis, ferroptosis, satellite glial cell death, tubarial dysfunction, and a coordinated diabetic secretory denervation syndrome.

Figure 1 autonomic circuits to the PPG — Figure 1. Autonomic convergence at the PPG: parasympathetic fibres synapse; sympathetic fibres pass through and arrive by internal- and external-carotid routes.

Figure 2 PPG trophic dependency — Figure 2. Sympathetic withdrawal remodels the nitrergic phenotype of PPG parasympathetic neurons; intra-ganglionic axo-axonal synapses are not claimed.

02 · Cell-death explorer

One demonstrated modality, several testable extensions

Click a modality to see its evidence status, predicted molecular markers, and why it matters to the PPG neuron–satellite glial cell unit.

Figure 3 cell death pathways — Figure 3. The manuscript distinguishes the experimentally demonstrated apoptotic route from predicted regulated cell-death pathways and the proposed neuron–SGC death cycle.

Figure 4 SGC loss — Figure 4. Proposed mechanisms by which satellite glial cell loss could destabilise the PPG microenvironment and drive secondary neuronal dysfunction.

03 · Diabetic secretory denervation syndrome

One ganglionic lesion, multiple secretory territories

The hypothesis predicts that PPG neurodegeneration should not produce isolated ocular disease. The same upstream lesion should produce correlated dysfunction across anatomically linked targets.

Figure 5 diabetic secretory denervation syndrome — Figure 5. Direct PPG target fields are separated from the proposed tubarial extension. The unifying prediction is correlated dysfunction across several territories rather than isolated dry eye.

04 · Threshold model

Reversible dysfunction may precede irreversible cell loss

The manuscript draws heavily on the two-phase diabetic nitrergic neuropathy model: an early functional phase with reduced nitrergic phenotype, followed by a later apoptotic phase that may represent a “point of no return.”

Early

Phenotypic decline

nNOS depletion and impaired nitrergic function may occur before neuronal loss.

16+

Weeks in STZ rats

The later phase is characterised by progressive loss of nNOS-positive PPG cell bodies.

~20%

TUNEL-positive

Approximately 20% of nNOS-positive neurons were TUNEL-positive by week 20 in the cited experimental series.

↓ reserve

Clinical threshold

The hypothesis predicts symptomatic disease once remaining ganglionic reserve can no longer sustain basal secretory output.

Interpretation: this framework explains why end-organ anti-inflammatory treatment may become insufficient if the primary deficit is upstream secretomotor denervation rather than inflammation alone.

05 · PPF block: therapeutic hypothesis

Could a pterygopalatine fossa block modulate the death cycle?

The manuscript treats this as a mechanistic proposal, not a demonstrated disease-modifying therapy. Local anaesthetic and corticosteroid actions are mapped onto candidate inflammatory nodes in the neuron–SGC cycle.

Local anaesthetic

Potential reduction of excitotoxic DAMP release and suppression of NF-κB/p38 inflammatory priming through SOCS3-related mechanisms.

HMGB1/TLR4 axis

A putative route by which local anaesthetics could reduce DAMP-driven glial activation.

Dexamethasone

Predicted suppression of NLRP3 assembly, caspase-1 activation, GSDMD cleavage, and pyroptotic cytokine release.

Important: no study has directly measured apoptosis, necroptosis, pyroptosis, or inflammasome activation in PPG tissue before and after PPF block. The therapeutic section is explicitly hypothesis-generating.

06 · Testable predictions

The paper is built around testable predictions that could confirm, refine, or falsify the proposed model.

The hypothesis generates specific anatomical, histological, functional, and clinical predictions rather than relying on a non-testable explanatory narrative.

Human PPG histologyDry-eye and diabetic cadaveric PPGs should show reduced neuronal density, altered SGC:neuron ratio, and a panel of cell-death markers.

Longitudinal diabetic modelsPPG neuron/SGC loss should covary with tear secretion, nasal mucociliary clearance, and palatal salivary flow.

Single-cell profilingscRNA-seq should reveal differentially vulnerable SGC and neuronal subtypes.

Multi-organ clinical correlationSchirmer testing, nasal saccharin transit time, and palatal salivary output should decline together if they share a PPG lesion.

Cerebrovascular linkMeasures of cerebral perfusion should correlate with secretory dysfunction if loss of PPG nitrergic vasodilator tone is clinically relevant.

Anatomical reservePartitioned PPGs and dispersed microganglia may modify severity, laterality, and response to focal interventions.

Tubarial territoryIf PPG innervation is confirmed, tubarial gland function should covary with other PPG-dependent secretory deficits.