Histamine-Induced Peripheral Priming Promotes Region-Specific Glial Remodelling and Protects Against Dopaminergic Injury in a Mouse Model of Parkinson’s Disease

Abstract Peripheral immune priming can induce long-lasting changes in brain innate immune responses. In neurological diseases, including Alzheimer’s disease and stroke, inflammatory priming has been associated with neuroprotection, likely through microglial reprogramming. Here, we evaluated whether repeated peripheral histamine exposure was associated with persistent glial morphometric remodelling and with an altered response to subsequent dopaminergic injury. Adult male mice received four consecutive daily intraperitoneal injections of histamine, lipopolysaccharide (LPS), used as a reference peripheral immune-stimulating condition, or PBS. Three weeks later, glial morphometry was assessed in the substantia nigra (SN) and striatum (ST). In a separate cohort, mice underwent intrastriatal 6-hydroxydopamine (6-OHDA) lesion three weeks after priming. Motor behaviour, nigrostriatal TH immunoreactivity, apomorphine-evoked striatal neuronal recruitment and glial morphometric response were evaluated two weeks later. Under non-lesioned conditions, histamine and LPS exposure were associated with persistent microglial morphometric remodelling in the SN, whereas comparable ST changes were detected only after LPS. Astrocytic GFAP-based measures showed modest, non-significant trends in the SN. Following 6-OHDA lesion, prior histamine or LPS exposure reduced apomorphine-induced rotational asymmetry and was associated with greater preservation of tyrosine hydroxylase (TH) immunoreactivity in the nigrostriatal system. Histamine priming additionally increased apomorphine-evoked recruitment of DARPP-32-positive striatal neurons and attenuated lesion-associated microglial changes in the SN and ST. Astrocytic responses after lesion were region-dependent. Repeated peripheral histamine exposure was associated with persistent, region-specific glial morphometric remodelling and attenuated behavioural and dopaminergic deficits following subsequent 6-OHDA injury. These findings are compatible with long-lasting histamine-associated neuroimmune conditioning, although the underlying cellular and molecular mechanisms and the causal contribution of glial remodelling remain to be established. Graphical Abstract Repeated peripheral histamine or LPS exposure is associated with long-lasting, region-specific glial remodelling and attenuated 6-OHDA-induced dopaminergic injury.