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Aims: In this original research communication, we assess the impact of shifting the window of glial HMOX1 overexpression in mice from early-to-midlife to mid-to-late life, resulting in two disparate conditions modeling schizophrenia (SCZ) and Parkinson's disease (PD). Mesolimbic hyperdopaminergia is a widely accepted feature of SCZ, while nigrostriatal hypodopaminergia is the sine qua non of idiopathic PD. Although the advent of parkinsonian features in SCZ patients after treatment with antidopaminergic agents is intuitive, subtle features of parkinsonism commonly observed in young, drug-naïve schizophrenics are not. Similarly, emergent psychosis in PD subjects receiving levodopa replacement is not unusual, whereas spontaneous hallucinosis in nonmedicated persons with idiopathic PD is enigmatic. Investigations using GFAP.HMOX1 mice may shed light on these clinical paradoxes. Results: Astroglial heme oxygenase-1 (HO-1) overexpression in mice throughout embryogenesis until 6 or 12 months of age resulted in hyperdopaminergia, hyperkinesia/stereotypy ameliorated with clozapine, deficient prepulse inhibition of the acoustic startle response, reduced preference for social novelty, impaired nest building, and cognitive dysfunction reminiscent of SCZ. On the contrary, astroglial HO-1 overexpression between 8.5 and 19 months of age yielded a PD-like behavioral phenotype with hypodopaminergia, altered gait, locomotor incoordination, and reduced olfaction. Innovation: We conjecture that region-specific disparities in the susceptibility of dopaminergic and other circuitry to the trophic and degenerative influences of glial HMOX1 induction may permit the concomitant expression of mixed SCZ and PD traits within affected individuals. Conclusion: Elucidation of these converging mechanisms may (i) help better understand disease pathogenesis and (ii) identify HO-1 as a potential therapeutic target in neurodevelopmental and neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Epigenetic influences mediating brain iron deposition, oxidative mitochondrial injury, and macroautophagy in Parkinson disease and related conditions remain enigmatic. Here, we show that selective overexpression of the stress protein, heme oxygenase-1 (HO-1) in astrocytes of GFAP.HMOX1 transgenic mice between 8.5 and 19 months of age results in nigrostriatal hypodopaminergia associated with locomotor incoordination and stereotypy; downregulation of tyrosine hydroxylase, DAT, LMX1B, Nurr1, Pitx3 and DJ-1 mRNA and/or protein; overproduction of α-synuclein and ubiquitin; oxidative stress; basal ganglia siderosis; mitochondrial damage/mitophagy; and augmented GABAergic systems (increased GABA, GAD67 and reelin). The neurophenotype of these GFAP.HMOX1 8.5-19m mice is highly consistent with parkinsonism and differs dramatically from the schizophrenia-like features previously documented in younger GFAP.HMOX1 0-12m mice. Common stressors may elicit either early-onset developmental (schizophrenia) or later-life degenerative (PD) brain disorders depending on whether the glial HO-1 response is engaged prior to or following the maturation of dopaminergic circuitry. Curtailment of glial HO-1 transduction at strategic points of the life course may confer neuroprotection in human degenerative and developmental central nervous system disorders. [ABSTRACT FROM AUTHOR]

Abstract Under stressful conditions, cellular heme catabolism to carbon monoxide, iron and biliverdin is mediated by the 32 kDa enzyme, heme oxygenase-1 (HO-1). A wide range of pro-oxidant and inflammatory stimuli act on diverse consensus sequences within the Hmox1 promoter to rapidly induce the gene. There is ample evidence attesting to the beneficial effects of HO-1 upregulation in brain. By converting pro-oxidant heme to the antioxidants, biliverdin and bilirubin, HO-1/biliverdin reductase may help restore a more favorable tissue redox microenvironment. Contrariwise, in some cell types and under certain circumstances, heme-derived carbon monoxide and iron may amplify intracellular oxidative stress and exacerbate the disease process. This inimical side of neural HO-1 has often been ignored in biomedical literature promulgating interventions aimed at boosting central HO-1 expression for the management of diverse CNS conditions and is the focus of the current review. A comprehensive model of astroglial stress is presented wherein sustained Hmox1 induction promotes oxidative mitochondrial membrane damage, iron sequestration and mitophagy (macroautophagy). The HO-1 mediated gliopathy renders nearby neuronal constituents vulnerable to oxidative injury and recapitulates 'core' neuropathological features of many aging-related neurodegenerative and some neurodevelopmental brain disorders. A balanced literature should acknowledge that, in a host of chronic human CNS afflictions, the glial HO-1 response may serve as a robust transducer of noxious stimuli, an important driver of relevant neuropathology and a potentially disease-modifying therapeutic target. [ABSTRACT FROM AUTHOR]

Schizophrenia is a neuropsychiatric disorder that features neural oxidative stress and glutathione (GSH) deficits. Oxidative stress is augmented in brain tissue of GFAP.HMOX1 transgenic mice which exhibit schizophrenia-relevant characteristics. The whey protein isolate, Immunocal® serves as a GSH precursor upon oral administration. In this study, we treated GFAP.HMOX1 transgenic mice daily with either Immunocal (33 mg/ml drinking water) or equivalent concentrations of casein (control) between the ages of 5 and 6.5 months. Immunocal attenuated many of the behavioral, neurochemical and redox abnormalities observed in GFAP.HMOX1 mice. In addition to restoring GSH homeostasis in the CNS of the transgenic mice, the whey protein isolate augmented GSH reserves in the brains of wild-type animals. These results demonstrate that consumption of whey protein isolate augments GSH stores and antioxidant defenses in the healthy and diseased mammalian brain. Whey protein isolate supplementation (Immunocal) may constitute a safe and effective modality for the management of schizophrenia, an unmet clinical imperative. [ABSTRACT FROM AUTHOR]