Monica R. Langley

Western-style diets cause disruptions in myelinating cells and astrocytes within the mouse CNS. CD38 has increased expression in the cuprizone and EAE demyelination models and is the main NAD ⁺ depleting enzyme in CNS tissue. Altered NAD ⁺ metabolism has been linked to both high fat consumption and Multiple Sclerosis (MS). We identified increased CD38 expression in the male mouse spinal cord following chronic high fat consumption or focal lysolecithin-induced demyelinating injury as well as in reactive astrocytes within an active MS lesion. CD38-catalytically inactive mice are significantly protected from high fat-induced NAD ⁺ depletion, oligodendrocyte loss, oxidative damage, and astrogliosis. 78c, a CD38 inhibitor, increased NAD ⁺ and attenuated neuroinflammatory changes in astrocytes induced by saturated fat. Conditioned media from saturated fat-treated astrocytes impaired oligodendrocyte differentiation pointing to indirect mechanisms of oligodendrogliopathy. Combined saturated fat and lysolecithin demyelination in cerebellar slices resulted in additional deficits in myelin proteins that were mitigated by concomitant 78c treatment. Importantly, oral 78c increased counts of oligodendrocytes and remyelinated axons after focal demyelination. Our findings suggest high fat diet impairs oligodendrocyte survival and differentiation through astrocyte-linked mechanisms mediated by the NAD ⁺ ase CD38, and highlight the use of CD38 inhibitors as potential therapeutic candidates to improve myelin regeneration.

Oral treatment with a brain-penetrant NLRP3 inhibitor has protective effects in preclinical models of Parkinson’s disease.

Aims: Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive motor deficits and degeneration of dopaminergic neurons. Caused by a number of genetic and environmental factors, mitochondrial dysfunction and oxidative stress play a role in neurodegeneration in PD. By selectively knocking out mitochondrial transcription factor A (TFAM) in dopaminergic neurons, the transgenic MitoPark mice recapitulate many signature features of the disease, including progressive motor deficits, neuronal loss, and protein inclusions. In the present study, we evaluated the neuroprotective efficacy of a novel mitochondrially targeted antioxidant, Mito-apocynin, in MitoPark mice and cell culture models of neuroinflammation and mitochondrial dysfunction. Results: Oral administration of Mito-apocynin (10 mg/kg, thrice a week) showed excellent central nervous system bioavailability and significantly improved locomotor activity and coordination in MitoPark mice. Importantly, Mito-apocynin also partially attenuated severe nigrostriatal degeneration in MitoPark mice. Mechanistic studies revealed that Mito-apo improves mitochondrial function and inhibits NOX2 activation, oxidative damage, and neuroinflammation. Innovation: The properties of Mito-apocynin identified in the MitoPark transgenic mouse model strongly support potential clinical applications for Mito-apocynin as a viable neuroprotective and anti-neuroinflammatory drug for treating PD when compared to conventional therapeutic approaches. Conclusion: Collectively, our data demonstrate, for the first time, that a novel orally active apocynin derivative improves behavioral, inflammatory, and neurodegenerative processes in a severe progressive dopaminergic neurodegenerative model of PD. Antioxid. Redox Signal. 27, 1048–1066.

Background: Parkinson disease (PD) is a neurodegenerative disorder that has been associated with many factors, including oxidative stress, inflammati

Hydrogen sulfide (H₂S) is a highly neurotoxic gas. It is the second most common cause of gas‐induced deaths. Beyond mortality, surviving victims of acute exposure may suffer long‐term neurological sequelae. There is a need to develop countermeasures against H₂S poisoning. However, no translational animal model of H₂S‐induced neurological sequelae exists. Here, we describe a novel mouse model of H₂S‐induced neurotoxicity for translational research. In paradigm I, C57/BL6 mice were exposed to 765 ppm H₂S for 40 min on day 1, followed by 15‐min daily exposures for periods ranging from 1 to 6 days. In paradigm II, mice were exposed once to 1000 ppm H₂S for 60 minutes. Mice were assessed for behavioral, neurochemical, biochemical, and histopathological changes. H₂S intoxication caused seizures, dyspnea, respiratory depression, knockdowns, and death. H₂S‐exposed mice showed significant impairment in locomotor and coordinated motor movement activity compared with controls. Histopathology revealed neurodegenerative lesions in the collicular, thalamic, and cortical brain regions. H₂S significantly increased dopamine and serotonin concentration in several brain regions and caused time‐dependent decreases in GABA and glutamate concentrations. Furthermore, H₂S significantly suppressed cytochrome c oxidase activity and caused significant loss in body weight. Overall, male mice were more sensitive than females. This novel translational mouse model of H₂S‐induced neurotoxicity is reliable, reproducible, and recapitulates acute H₂S poisoning in humans.

Quercetin, one of the major flavonoids in plants, has been recently reported to have neuroprotective effects against neurodegenerative processes. However, since the molecular signaling mechanisms governing these effects are not well clarified, we evaluated quercetin's effect on the neuroprotective signaling events in dopaminergic neuronal models and further tested its efficacy in the MitoPark transgenic mouse model of Parkinson's disease (PD). Western blot analysis revealed that quercetin significantly induced the activation of two major cell survival kinases, protein kinase D1 (PKD1) and Akt inMN9D dopaminergic neuronal cells. Furthermore, pharmacological inhibition or siRNAknockdown ofPKD1 blocked the activation of Akt, suggesting thatPKD1 acts as an upstream regulator of Akt in quercetin‐mediated neuroprotective signaling. Quercetin also enhanced cAMP response‐element binding protein phosphorylation and expression of the cAMP response‐element binding protein target gene brain‐derived neurotrophic factor. Results fromqRT‐PCR, Western blot analysis, mtDNAcontent analysis, and MitoTracker assay experiments revealed that quercetin augmented mitochondrial biogenesis. Quercetin also increased mitochondrial bioenergetics capacity and protectedMN9D cells against 6‐hydroxydopamine‐induced neurotoxicity. To further evaluate the neuroprotective efficacy of quercetin against the mitochondrial dysfunction underlyingPD, we used the progressive dopaminergic neurodegenerative MitoPark transgenic mouse model ofPD. Oral administration of quercetin significantly reversed behavioral deficits, striatal dopamine depletion, andTHneuronal cell loss in MitoPark mice. Together, our findings demonstrate that quercetin activates thePKD1‐Akt cell survival signaling axis and suggest that further exploration of quercetin as a promising neuroprotective agent for treatingPDmay offer clinical benefits. image

Prokineticin-2 (PK2), a recently discovered secreted protein, regulates important physiological functions including olfactory biogenesis and circadian rhythms in the CNS. Interestingly, although PK2 expression is low in the nigral system, its receptors are constitutively expressed on nigrostriatal neurons. Herein, we demonstrate that PK2 expression is highly induced in nigral dopaminergic neurons during early stages of degeneration in multiple models of Parkinson’s disease (PD), including PK2 reporter mice and MitoPark mice. Functional studies demonstrate that PK2 promotes mitochondrial biogenesis and activates ERK and Akt survival signalling pathways, thereby driving neuroprotection. Importantly, PK2 overexpression is protective whereas PK2 receptor antagonism exacerbates dopaminergic degeneration in experimental PD. Furthermore, PK2 expression increased in surviving nigral dopaminergic neurons from PD brains, indicating that PK2 upregulation is clinically relevant to human PD. Collectively, our results identify a paradigm for compensatory neuroprotective PK2 signalling in nigral dopaminergic neurons that could have important therapeutic implications for PD.

Mitochondrial dysfunction, oxidative stress and neuroinflammation have been implicated as key mediators contributing to the progressive degeneration of dopaminergic neurons in Parkinson’s disease (PD). Currently, we lack a pharmacological agent that can intervene in all key pathological mechanisms, which would offer better neuroprotective efficacy than a compound that targets a single degenerative mechanism. Herein, we investigated whether mito-apocynin (Mito-Apo), a newly-synthesized and orally available derivative of apocynin that targets mitochondria, protects against oxidative damage, glial-mediated inflammation and nigrostriatal neurodegeneration in cellular and animal models of PD. Mito-Apo treatment in primary mesencephalic cultures significantly attenuated the 1-methyl-4-phenylpyridinium (MPP⁺)-induced loss of tyrosine hydroxylase (TH)-positive neuronal cells and neurites. Mito-Apo also diminished MPP⁺-induced increases in glial cell activation and inducible nitric oxide synthase (iNOS) expression. Additionally, Mito-Apo decreased nitrotyrosine (3-NT) and 4-hydroxynonenol (4-HNE) levels in primary mesencephalic cultures. Importantly, we assessed the neuroprotective property of Mito-Apo in the MPTP mouse model of PD, wherein it restored the behavioral performance of MPTP-treated mice. Immunohistological analysis of nigral dopaminergic neurons and monoamine measurement further confirmed the neuroprotective effect of Mito-Apo against MPTP-induced nigrostriatal dopaminergic neuronal loss. Mito-Apo showed excellent brain bioavailability and also markedly attenuated MPTP-induced oxidative markers in the substantia nigra (SN). Furthermore, oral administration of Mito-Apo significantly suppressed MPTP-induced glial cell activation, upregulation of proinflammatory cytokines, iNOS and gp91phox in IBA1-positive cells of SN. Collectively, these results demonstrate that the novel mitochondria-targeted compound Mito-Apo exhibits profound neuroprotective effects in cellular and pre-clinical animal models of PD by attenuating oxidative damage and neuroinflammatory processes.