N‐3 PUFA‐Deficiency in Early Life Exhibits Aggravated MPTP‐Induced Neurotoxicity in Old Age while Supplementation with DHA/EPA‐Enriched Phospholipids Exerts a Neuroprotective Effect

Abstract

Introduction: Malnutrition in early life affects the growth and development of fetus and children, which has a long-term impact on adult health. Previous studies reveal a relationship between dietary omega-3 polyunsaturated fatty acid (n-3 PUFA) content, brain development, and the prevalence of neurodevelopmental disorders and inflammation. However, it is unclear about the effect of n-3 PUFA-deficiency in early life on the development of Parkinson's disease (PD) in old age, as well as the neuroprotective effect of DHA-and EPA-enriched phospholipids (DHA/EPA-PLs) supplemented in old age in long-term n-3 PUFA-deficient mice. Methods and Results: The PD mice induced by 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) in n-3 PUFA-adequate (N) and -deficient (DEF) group are supplemented with a DHA/EPA-PLs diet for 2 weeks (N+DPL, DEF+DPL). DHA/EPA-PLs supplementation significantly protects against MPTP-induced impairments. The DEF+DPL group shows poorer motor performance, the loss of dopaminergic neurons, mitochondrial dysfunction, and neurodevelopment delay than the N+DPL group, and still did not recover to the Control level. Conclusions: Dietary n-3 PUFA-deficiency in early life exhibits more aggravated MPTP-induced neurotoxicity in old age, than DHA/EPA-PLs supplementation recovers brain DHA levels and exerts neuroprotective effects in old age in long-term n-3 PUFA-deficient mice, which might provide a potential dietary guidance.

N-3 PUFA Deficiency from Early Life to Adulthood Exacerbated Susceptibility to Reactive Oxygen Species-Induced Testicular Dysfunction in Adult Mice

“…43 N-3 PUFA deficiency could alter mitochondrial membrane permeability and potential by altering the structure of apoptosis-related proteins, for instance, caspase 3 and interfering with the expression of pro-apoptotic protein Bax and anti-apoptotic protein Bcl-2. 14,44 Besides, the phosphorylation activation of the MAPK signal could be inhibited by n-3 PUFAs. The mechanism study confirmed that the deficiency of n-3 PUFAs in testis increased caspase-dependent apoptosis and MAPK pathway induced by oxidative stress.…”

“…Furthermore, studies have shown that apoptosis mediated by caspase 3,9 and MAPK pathway (ERK/JNK/p38) plays a critical role in testicular injury. , Bcl-2 competes with Bax on the outer mitochondrial membrane to decrease the mitochondrial permeability to reduce the release of apoptotic signal molecules . N-3 PUFA deficiency could alter mitochondrial membrane permeability and potential by altering the structure of apoptosis-related proteins, for instance, caspase 3 and interfering with the expression of pro-apoptotic protein Bax and anti-apoptotic protein Bcl-2. , Besides, the phosphorylation activation of the MAPK signal could be inhibited by n-3 PUFAs. The mechanism study confirmed that the deficiency of n-3 PUFAs in testis increased caspase-dependent apoptosis and MAPK pathway induced by oxidative stress .…”

“…Dietary n-3 PUFAs are essential for the functional maturation of the brain and peripheral tissue, and low maternal consumption of n-3 PUFAs has been associated with neurodevelopmental disorders in offspring. Previous studies have reported that n-3 PUFA deficiency early in life significantly reduced n-3 PUFA levels in the brain and led to increased susceptibility to 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity and scopolamine-induced cognitive decline, as well as the high-fat diet-induced metabolic syndrome in adulthood. − Decreased n-3 PUFA levels in the testis may adversely affect testicular functional properties, including spermatogenesis and androgen production. The replicative processes of spermatogenesis imply the highest rate of mitochondrial oxygen consumption and reactive oxygen species generation.…”

Fish oil supplementation, physical activity and risk of incident Parkinson’s disease: results of longitudinal analysis from the UK Biobank

“…Omega-3 fatty acids have been shown to inhibit microglial cell activity and neuroinflammation, protect astrocyte function, and produce neurotrophic factors that improve neurodegeneration and normalize neurotransmission ( McCarty and Lerner, 2020 ). Recent studies have also shown that omega-3 fatty acids improve PD by inhibiting pro-inflammatory cytokine release, restoring mitochondrial function and membrane fluidity, and reducing levels of oxidant production ( Wu et al, 2021 ). The omega-3 fatty acid docosahexaenoic acid increases dopamine synthesis in striatal motor areas by phosphorylating the restrictive catecholamine synthase tyrosine hydroxylase in a manner dependent on second messenger-linked protein kinases (PKA and PKC), thus preventing deficits in postural stability, gait integrity, and dopamine neurochemistry ( Chitre et al, 2020 ).…”

Supplementation of n-3 PUFAs in Adulthood Attenuated Susceptibility to Pentylenetetrazol Induced Epilepsy in Mice Fed with n-3 PUFAs Deficient Diet in Early Life

“…Evidence suggests that inadequate levels of n-3 PUFAs may represent a risk factor for these disorders. Wang et al reported that dietary n-3 PUFA-deficiency in early life exhibited more aggravated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity and increased vulnerability to scopolamine-induced cognitive impairment in male offspring [ 6 , 7 ]. Furthermore, maternal dietary n-3 PUFA deficiency increases microglia-mediated phagocytosis of synaptic elements in the rodent developing hippocampus, partly through the activation of 12/15-lipoxygenase (LOX)/12-hydroxyeicosatetraenoic acid (HETE) signaling, altering neuronal morphology and affecting the cognitive performance of the offspring [ 8 ].…”