Table 1.

The molecular mechanisms involved in manganese (Mn)-induced toxicity in various neural cell types such as microglia, astrocytes, and neurons and in multiple regions of the brain.

Experimental Model	Species	Mn (Dosage/Concentration)	Cytotoxicity Mechanisms	Disease Model	References
Neural cell type
Microglia	Mouse (N9), Mouse (BV2)	MnCl2 (50–1000 µM)	↑TNF-α, ↑ILs, ↑interferons ↑NF-κB activation	Mn toxicity	[93,125,128]
Microglia	Mouse (N9), Rat	MnCl2 (30 µM)	↑TNF-α, ↑IL-1β	Mn toxicity	[125,127]
Microglia	Human (HMC3)	MnCl2 (250 µM)	↑LRRK2 expression and kinase activity ↑ROS, ↑TNF-α, ↑apoptosis	Mn toxicity	[131]
Astrocytes	Mice	MnCl2 (0.1–10 µM)	↑Cyclooxygenase 2, ↑iNOS, ↑NF-κB activation, ↑inflammation	Mn toxicity	[118,120,121,122]
Astrocytes	Mouse	MnCl2 (50 µM)	↑Inflammation, ↑iNOS, ↑NO	Mn toxicity	[123]
Astrocytes	Rat, Mice	MnCl2 (5, 50 µM)	↑TNF-α, ↑IL-1β, ↑iNOS	Mn toxicity	[20,118,124,125,126]
Astrocytes	Rat, Human	MnCl2 (250 µM)	↓Glutamate reuptake, ↓EAAT1/GLAST, ↓EAAT2/GLT-1, ↑YY1, ↑HDAC-YY1 interaction	Mn toxicity	[149,150]
Astrocytes	Rat	MnCl2 (100–200 µM)	↓Glutamate reuptake, ↓SOD activity, ↓GPx activity, ↑LDH release, ↑IL-6	Mn toxicity	[99]
Astrocytes	Rat	MnCl2 (100, 500, 1000 µM)	↑F2-isoprostanes, ↑lipid peroxidation	Mn toxicity	[107]
Astrocytes	Human (U87)	MnCl2 (400, 800, 2000 µM)	↓Glutathione	Mn toxicity	[100]
Neurons
Cortical Neuron	rat	MnCl2 (500 µM)	↑ROS production, ↑F2-isoprostanes, ↓ATP production	Mn toxicity	[22]
Dopaminergic	Human (SH-SY5Y)	MnCl2 (800 µM)	↑ROS production, ↑lipid peroxidation, ↓ATP levels, ↓mitochondrial membrane potential	Mn toxicity; PD	[101]
Dopaminergic	Human (SH-SY5Y)	MnCl2 (2–125 µM)	↑DNA damage, ↑oxidative stress	Mn toxicity; PD	[23]
Dopaminergic	Rat (N27)	MnCl2 (300 µM)	↑Cytochrome c release, ↑caspase-3 activation, ↑DNA damage, ↑ROS, ↑apoptosis, ↑αSyn aggregation	Mn toxicity	[94]
Dopaminergic	Rat (N27)	MnCl2 (10–5000 µM)	↑ROS, ↑mitochondria damage, ↑apoptosis, ↑PKCδ activation	Mn toxicity	[95,96]
Catecholaminergic/Dopaminergic	Mouse (CAD), Human (LUHMES)	MnCl2 (250 µM)	↓TH, ↓REST, ↓NRF2, ↓catalase, ↓HO-1 ↑oxidative stress, ↑inflammation	Mn toxicity; PD	[8]
Dopaminergic	Rat (PC12)	MnCl2 (100 µM)	↑TH phosphorylation, ↑cytotoxicity	Mn toxicity; PD	[141]
Dopaminergic	C. elegans	MnCl2 (40 mM)	↑oxidative stress	Mn toxicity; PD	[98]
Cholinergic	Mouse (SN56)	MnCl2 (1–200 µM)	↑Aβ peptides misfolding and aggregation	AD	[179]
Neuron	Mouse, Rat	MnCl2 (100, 500, 1000 µM)	↑F2-isoprostanes, ↑lipid peroxidation	Mn toxicity	[106]
Neuron	Rat (PC12)	MnCl2 (100–500 µM)	↑Tau phosphorylation, ↑impaired tau degradation/aggregation, ↑ERK/GSK-3β activation, ↑cytotoxicity	AD	[180]
Dopaminergic	Rat (MES 23.5)	MnCl2 (200–600 µM)	↑αSyn levels, ↑p38 activation, ↑NF-κB activation, ↑NO, ↑apoptosis	Mn toxicity; PD	[167]
Organotypic Brain Slices	Rat	MnCl2 (400 µM)	↑ROS, ↑apoptosis, ↑LDH release, ↓SOD activity, ↑αSyn levels	Mn toxicity; PD	[166]
Dopaminergic	Human (SH-SY5Y)	MnCl2 (500 µM)	↑Apoptosis, ↑caspase 3, ↑αSyn levels	Mn toxicity; PD	[169]
Dopaminergic	Mouse (MN9D)	MnCl2 (300 μM)	↑Exosome release, ↑cytotoxicity, ↑Rab27a	Mn toxicity	[172]
Dopaminergic	Human (LUHMES), Mouse (MN9D)	MnCl2 (10 mM)	↑αSyn misfolding, ↑αSyn release, ↑inflammation	Mn toxicity	[173]
Brain regions
Striatum, brain stem	Rat	MnCl2 (25 mg/kg)	↓Glutathione synthesis, ↓energy ↑hypoxanthine, ↑xanthine, ↑uric acid		[102]
Basal ganglia	Human	NA	↑Astrogliosis	Mn toxicity; PD	[117]
Basal ganglia (Striatum); Substantia nigra	Rat (neonate, adult)	MnCl2 (10 mg/kg)	↓DA levels	Mn toxicity; PD	[132,133]
Striatum	Rat	Mn (100 mg/kg)	↓DA levels and stores, ↓DA turnover, ↓DA release, ↑behavioral deficits	Mn toxicity; PD	[134,135,136]
Globus pallidus (Striatum), Midbrain	Human	NA	↑Mn levels, ↓DA transporter	Mn toxicity	[111]
Striatum	Rat	MnCl2 (5–20 mg/kg, daily, 20 d)	↑Motor deficits, ↑oxidative stress	Mn toxicity; PD	[21]
Striatum	Rat	MnCl2 (0.5–2 µmol/µL)	↑Excitotoxic lesions; ↑oxidative stress, ↑mitochondrial impairment	Mn toxicity	[146]
Striatum	Rat	MnCl2 (1 mg/mL)	↓ChAT, ↓ACh levels,	Mn toxicity	[155]
Striatum	Mouse	MnCl2 (50, 100, and 200 μmol/kg)	↑Autophagy dysregulation, ↑cell injury. ↑αSyn	Mn toxicity; PD	[168]
Hippocampus	Mouse	MnCl2 (100 µmol/kg, 5×/week, 6 weeks)	↑Impaired NMDA phosphorylation, ↑memory dysfunction, ↑αSyn dysregulation	Mn toxicity; AD	[148]
Whole brain	Rat	MnCl2 (30 mg/kg)	↓AChE, ↑oxidative and nitrosative stress, ↑intracellular Ca2+ accumulation	Mn toxicity	[154]
Whole brain	Rat	MnCl2 (3 mg/mL)	↓GABA, ↑seizure duration, ↓seizure threshold	Mn toxicity	[25]
Forebrain	Rat	MnCl2 (10 mM)	↓GABA uptake	Mn toxicity	[159]
Thalamus	Rat	MnCl2 (1 g/L)	↑GABA	Mn toxicity	[160]
Substantia nigra	Mouse	MnCl2 (30 mg/kg, daily/3 wks)	↓TH, ↓EAAT1/GLAST, ↓EAAT2/GLT-1, ↑YY1, ↑HDAC-YY1 interaction, ↑motor deficits, ↑microglial activation	Mn toxicity; PD	[8]
Midbrain, cerebellum	Mouse	MnCl2 (10 mg/mL)	↓ChAT, ↑impaired choline uptake	Mn toxicity; encephalopathy	[156]
Hippocampus, cortex, and basal ganglia	Rat	MnCl2	↓Choline transporter, ↓choline uptake, ↓homovanillic acid	Mn toxicity	[157]
Prefrontal cortex	Mouse	MnCl2 (5 mg/kg, daily/22 d)	↓ACh activity, ↓nicotinic ACh receptors, ↑impaired spatial memory	Mn toxicity; AD	[158]
Frontal Cortex	Nonhuman primate	Mn (3.3–5.0, 5.0–6.7, 8.3–10 mg Mn/kg)	↑αSyn aggregation, ↑apoptosis	Mn toxicity; PD	[165]
Frontal cortex	Nonhuman primate	NA	↑Aβ precursor protein 1, ↑Aβ expression, ↑cytotoxicity	AD	[176,177]
Parietal cortex	Human	NA	↑Mn levels, ↑AD pathology, ↑impaired Aβ and ApoE function	AD	[174]
Cerebral cortex, hippocampus	Mouse	MnCl2 (0.36 mg/mL, 5 mos.)	↑Aβ expression, ↑β- and γ-secretase cleavage activities	AD	[178]
Blood	Human	NA	↑Mn levels, ↑impaired Aβ degradation/aggregation, ↑cognitive impairment	AD	[175]

↑: increased. ↓: decreased. NA, not applicable/not available. CAD: Cath.a differentiated. LRRK2: leucine rich repeat kinase 2. LUHMES: Lund human mesencephalic. TNF-α: tumor necrosis factor alpha. NF-κB: nuclear factor kappa-light-chain enhancer of B cells. IL-1β: interleukin 1β. IL-6: interleukin 6. iNOS: inducible nitric oxide synthase. NO: nitric oxide SOD: superoxide dismutase. GPx: glutathione peroxidase. LDH: lactate dehydrogenase. ROS: reactive oxygen species. EAAT1/2: excitatory amino acid transporter 1/2. GLAST: glutamate aspartate transporter 1. GLT: glutamate transporter 1 PKC: protein kinase C. GSH: glutathione. NRF2: Nuclear factor erythroid 2-related factor 2. HO-1: Heme oxygenase-1. REST: repressor element-1 silencing transcription factor. TH: tyrosine hydroxylase. DA: dopamine. αSyn: α-synuclein. Aβ: amyloid-β. ApoE: apolipoprotein E. ChAT: choline acetyltransferase. ACh: acetylcholine. GABA: gamma aminobutyric acid. ERK: extracellular signal-regulated kinase: GSK-3β: HDAC: histone deacetylase. YY1: Yin Yang 1. NMDA: N-methyl D-aspartate. PD: Parkinson’s disease. AD: Alzheimer’s disease.