Neuroprotective Effects of Nicotinamide against MPTP-Induced Parkinson’s Disease in Mice: Impact on Oxidative Stress, Neuroinflammation, Nrf2/HO-1 and TLR4 Signaling Pathways

Rehman, Inayat Ur; Khan, Amjad; Ahmad, Riaz; Choe, Kyonghwan; Park, Hyun Young; Lee, Hyeon Jin; Atiq, Abubakar; Park, Jungsung; Hahm, Jong Ryeal; Kim, Myeong Ok

doi:10.3390/biomedicines10112929

Cited by 17 publications

(8 citation statements)

References 81 publications

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“…Pre-injection of NAD in the striatum of the 6-hydroxydopamine (a neurotoxin acting on mitochondrial Complex I) mouse model of Parkinson's disease ameliorated motor deficits and dopaminergic neuronal damage in the substantia nigra and striatum [ 51 ]. Additionally, in systemic MPTP models of Parkinson's disease, the administration of NAM resulted in the dose-dependent sparing of striatal dopamine levels and substantia nigra neurons [ 2 ], and also ameliorated Parkinsonian motor symptoms [ 48 ]. Parkinson’s disease clinical trials using NAM or other NAD-boosting agents are ongoing [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Intravitreal MPTP drives retinal ganglion cell loss with oral nicotinamide treatment providing robust neuroprotection

Rombaut,

Jovancevic,

Wong

et al. 2024

acta neuropathol commun

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Neurodegenerative diseases have common underlying pathological mechanisms including progressive neuronal dysfunction, axonal and dendritic retraction, and mitochondrial dysfunction resulting in neuronal death. The retina is often affected in common neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. Studies have demonstrated that the retina in patients with Parkinson’s disease undergoes changes that parallel the dysfunction in the brain. These changes classically include decreased levels of dopamine, accumulation of alpha-synuclein in the brain and retina, and death of dopaminergic nigral neurons and retinal amacrine cells leading to gross neuronal loss. Exploring this disease's retinal phenotype and vision-related symptoms is an important window for elucidating its pathophysiology and progression, and identifying novel ways to diagnose and treat Parkinson’s disease. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is commonly used to model Parkinson’s disease in animal models. MPTP is a neurotoxin converted to its toxic form by astrocytes, transported to neurons through the dopamine transporter, where it causes mitochondrial Complex I inhibition and neuron degeneration. Systemic administration of MPTP induces retinal changes in different animal models. In this study, we assessed the effects of MPTP on the retina directly via intravitreal injection in mice (5 mg/mL and 50 mg/mL to 7, 14 and 21 days post-injection). MPTP treatment induced the reduction of retinal ganglion cells—a sensitive neuron in the retina—at all time points investigated. This occurred without a concomitant loss of dopaminergic amacrine cells or neuroinflammation at any of the time points or concentrations tested. The observed neurodegeneration which initially affected retinal ganglion cells indicated that this method of MPTP administration could yield a fast and straightforward model of retinal ganglion cell neurodegeneration. To assess whether this model could be amenable to neuroprotection, mice were treated orally with nicotinamide (a nicotinamide adenine dinucleotide precursor) which has been demonstrated to be neuroprotective in several retinal ganglion cell injury models. Nicotinamide was strongly protective following intravitreal MPTP administration, further supporting intravitreal MPTP use as a model of retinal ganglion cell injury. As such, this model could be utilized for testing neuroprotective treatments in the context of Parkinson’s disease and retinal ganglion cell injury.

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Section: Discussionmentioning

confidence: 99%

Intravitreal MPTP drives retinal ganglion cell loss with oral nicotinamide treatment providing robust neuroprotection

Rombaut,

Jovancevic,

Wong

et al. 2024

acta neuropathol commun

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“…Western blot analysis was carried out, as previously described [ 44 , 45 , 46 ]. Briefly, a Bio-Rad protein assay tool (Bio-Rad Laboratories, Hercules, CA, USA) was used to assess the protein concentrations.…”

Section: Methodsmentioning

confidence: 99%

Vitamin E Analog Trolox Attenuates MPTP-Induced Parkinson’s Disease in Mice, Mitigating Oxidative Stress, Neuroinflammation, and Motor Impairment

Atiq

Lee

Khan

et al. 2023

IJMS

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Trolox is a potent antioxidant and a water-soluble analog of vitamin E. It has been used in scientific studies to examine oxidative stress and its impact on biological systems. Trolox has been shown to have a neuroprotective effect against ischemia and IL-1β-mediated neurodegeneration. In this study, we investigated the potential protective mechanisms of Trolox against a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson’s disease mouse model. Western blotting, immunofluorescence staining, and ROS/LPO assays were performed to investigate the role of trolox against neuroinflammation, the oxidative stress mediated by MPTP in the Parkinson’s disease (PD) mouse model (wild-type mice (C57BL/6N), eight weeks old, average body weight 25–30 g). Our study showed that MPTP increased the expression of α-synuclein, decreased tyrosine hydroxylase (TH) and dopamine transporter (DAT) levels in the striatum and substantia nigra pars compacta (SNpc), and impaired motor function. However, Trolox treatment significantly reversed these PD-like pathologies. Furthermore, Trolox treatment reduced oxidative stress by increasing the expression of nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Lastly, Trolox treatment inhibited the activated astrocytes (GFAP) and microglia (Iba-1), also reducing phosphorylated nuclear factor-κB, (p-NF-κB) and tumor necrosis factor-alpha (TNF-α) in the PD mouse brain. Overall, our study demonstrated that Trolox may exert neuroprotection on dopaminergic neurons against MPTP-induced oxidative stress, neuroinflammation, motor dysfunction, and neurodegeneration.

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“…FoxOs are intimately tied to the pathways of programmed cell death. Blockade of FoxO transcription factor activity can inhibit microglial cell apoptotic death during ROS and Aβ exposure [343,344,[349][350][351], foster the protective effects of metabotropic glutamate receptors [259,352], and prevent neuronal apoptotic cell loss through nicotinamide adenine dinucleotide (NAD + ) precursors [86,162,198,213,[353][354][355][356][357][358]. For example, nicotinamide can block FoxO protein activity [329,359] and is protective through two mechanisms of post-translational modification of FoxO3a [50, 186,317].…”

Section: Mammalian Forkhead Transcription Factors and Multiple Sclerosismentioning

confidence: 99%

Cognitive Impairment in Multiple Sclerosis

Maiese

2023

Bioengineering

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Almost three million individuals suffer from multiple sclerosis (MS) throughout the world, a demyelinating disease in the nervous system with increased prevalence over the last five decades, and is now being recognized as one significant etiology of cognitive loss and dementia. Presently, disease modifying therapies can limit the rate of relapse and potentially reduce brain volume loss in patients with MS, but unfortunately cannot prevent disease progression or the onset of cognitive disability. Innovative strategies are therefore required to address areas of inflammation, immune cell activation, and cell survival that involve novel pathways of programmed cell death, mammalian forkhead transcription factors (FoxOs), the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), and associated pathways with the apolipoprotein E (APOE-ε4) gene and severe acute respiratory syndrome coronavirus (SARS-CoV-2). These pathways are intertwined at multiple levels and can involve metabolic oversight with cellular metabolism dependent upon nicotinamide adenine dinucleotide (NAD+). Insight into the mechanisms of these pathways can provide new avenues of discovery for the therapeutic treatment of dementia and loss in cognition that occurs during MS.

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Neuroprotective Effects of Nicotinamide against MPTP-Induced Parkinson’s Disease in Mice: Impact on Oxidative Stress, Neuroinflammation, Nrf2/HO-1 and TLR4 Signaling Pathways

Cited by 17 publications

References 81 publications

Intravitreal MPTP drives retinal ganglion cell loss with oral nicotinamide treatment providing robust neuroprotection

Intravitreal MPTP drives retinal ganglion cell loss with oral nicotinamide treatment providing robust neuroprotection

Vitamin E Analog Trolox Attenuates MPTP-Induced Parkinson’s Disease in Mice, Mitigating Oxidative Stress, Neuroinflammation, and Motor Impairment

Cognitive Impairment in Multiple Sclerosis

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