Nanoparticles in Combating Neuronal Dysregulated Signaling Pathways: Recent Approaches to the Nanoformulations of Phytochemicals and Synthetic Drugs Against Neurodegenerative Diseases

Figures & data

Figure 1 Dysregulated signaling pathways in NDDs.

Abbreviations: AD, Alzheimer’s disease; ALS, amyotrophic lateral sclerosis; Cyt c, cytochrome c; ERK, extracellular signal-regulated kinase; HD, Huntington’s disease; iNOS, inducible nitric oxide synthase; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PD, Parkinson’s disease; PI3K, phosphoinositide 3-kinases; RNS, reactive nitrogen species; ROS, reactive oxygen species; STAT, signal transducer and activator of transcription.

Figure 2 The role of nanoparticles in combating NDDs-associated neuroinflammation, neuronal oxidative stress, and neuroapoptosis.

Abbreviations: Ag, silver; AMPK, AMP-activated protein kinase; ARE, antioxidant response element; Au, gold; CAT, catalase; CeO, cerium oxide; CeO2, cerium dioxide; COX, cyclooxygenase; Cu, copper; ERK, extracellular signal-regulated kinase; Fe2O3, Iron oxide; IL, interleukin; iNOS, inducible nitric oxide synthase; JAK, Janus kinase; MAPK, mitogen-activated protein kinase; MgO, magnesium oxide; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NPs, nanoparticles; Nrf2, nuclear factor-erythroid factor 2-related factor 2; PI3K, phosphoinositide 3-kinases; PLGA, poly(lactic-co-glycolic acid); Pt, platinum; RNS, reactive nitrogen species; ROS, reactive oxygen species; Se, selenium; SOD, superoxide dismutase; STAT, signal transducer and activator of transcription; TiO2, titanium dioxide; TNF-α, tumor necrosis factor-alpha; ZnO, zinc oxide.

Table 1 Nanoformulations of Phytochemicals and Synthetic Drugs in Combating AD and PD

Disease	Component	Nano Vehicle/Method	Study Type	Results	References
AD	Phytochemicals Nanoformulations
	Resveratrol	SLNs; ASDs	In vitro: endothelial cells; In vivo: Aβ/APP/PS1 mouse	↓formation of Aβ (1–42) aggregates, ↓quick clearance, ↓Aβ plaque density in the cortex, caudoputamen, and hippocampus	[^Citation126,^Citation184]
		NLCs	In vitro: fresh nasal mucosa of sheep; In vivo: male Sprague-Dawley rats	↑memory function, ↑permeation across nasal mucosa via decreasing the crystallinity of particles through a lipid-oil mixture	[^Citation127]
	Curcumin	PLGA; ASDs	In vitro/ in vivo: Tg2576 mice	↑working and recall memory via activating canonical Wnt/β-catenin pathway, ↑curcumin bioavailability, ↓rate of amyloid and plaque burden	[^Citation129,^Citation184]
		PLGA	In vitro: SK-N-SH cells, a human neuroblastoma cell line	↑curcumin stability	[^Citation131]
		PLGA-PEG-B6	In vitro: HT22 cells	↑cellular absorption, ↑blood compatibility	[^Citation134]
			In vivo: APP/PS1 mice	↑spatial learning and memory performance	[^Citation134]
			Ex vivo	↓hippocampus-amyloid production and deposit, ↓tau hyperphosphorylation	[^Citation134]
		PLGA	In vitro/in vivo: Wistar rats	↑NSC proliferation and neuronal differentiation in the hippocampus	[^Citation133]
		PLGA	In vivo: Wistar rats	↑hippocampus neurogenesis, cognition, and memory, ↑canonical Wnt/β-catenin pathway	[^Citation133]
		PLGA	In vitro: rat hippocampal cells	↓Aβ aggregates	[^Citation132]
		Nanoliposomes	In vitro: hAPPsw SH-SY5Y cell; In vivo: APP/PS1 mice	↓Aβ-induced toxicity, ↓Aβ deposits	[^Citation135]
	Naringenin	NEs	In vitro: SH-SY5Y cells	↓APP, ↓BACE, ↓tau phosphorylation	[^Citation136]
	Quercetin	PLGA; ASDs	In vitro: SH-SY5Y cells; In vivo: Aβ/C. elegan CL2006	Neurotoxicity of the Zn^2+-Aβ42 system, ↑neuron cell survival by suppressing Zn^2+-AB42 system, ↓aggregation of proteins	[^Citation140,^Citation184]
		PLGA-NPs	In vivo: APP/PS1 mice	↑cognitive functions and memory	[^Citation140]
		NPQ	In vivo: SAMP8 mice	↑oral absorption, ↑bioavailability, ↑cognitive and memory	[^Citation137]
		NPs	In vivo: male Albino Wistar rats	↑residence period in the systemic circulation, ↑ bioavailability	[^Citation139]
		Cyclodextrin-dodecyl carbonate nanoparticles	In vitro: SH-SY5Y cells	↓TLR4 and COX-2 signaling pathway, ↑BBB penetration, ↑bioavailability	[^Citation138]
	Rosmarinic acid	CRM197-ApoE-PAAM-CH-PLGA	In vitro: SK-N-MC cells	↓degeneration of Aβ-insulted neurons, ↑BBB transportation, ↓caspase-3, and c-Jun	[^Citation141]
	Epigallocatechin 3-gallate	Nanolipidic	In vitro: murine neuroblastoma cells; In vivo: male Sprague Dawley rats	↑neuronal α-secretase, ↑oral bioavailability	[^Citation142]
		Nano	In vitro: SH-SY-5Y cell	↓cellular toxicity, ↓Al^3+-induced Aβ42 fibrillation, and neurotoxicity	[^Citation143]
		Stabilized selenium nanoparticles coated with Tet-1 peptide	In vitro: PC12 cells	↓Aβ fibrillation, Aβ fibrils into harmless aggregates efficiently	[^Citation144]
	Ginsenoside Rg3	PLGA	In vitro: C6 rat glial cells and THP-1 human monocytic cells line	↑BBB permeability, ↓formation of Aβ plaques, and eventual neurodegeneration	[^Citation150]
	Ferulic acid	SLN	In vitro: human neuroblastoma cells (LAN 5)	↓ROS compared cells	[^Citation185]
	Berberine	MWCNTs	In vitro: SH-SY5Y cells; In vivo: male Wistar rats	↑memory function recovery, ↑biochemical levels in brain tissue, and ↓Aβ	[^Citation148]
	Sesamol	SLN	In vivo: male Wistar rats	↓neuronal malfunction, ↓ memory impairments by reducing oxidative stress	[^Citation146]
	Huperzine A	Lf-TMC NPs	In vitro/ex vivo: 16HBE and SH-SY5Y cell lines	↑mucoadhesion, ↑widely dispersed in the brain over a long period	[^Citation149]
	Nanoformulations of synthetic drugs
	Memantine	PEG–PLGA	In vitro/in vivo: APP/PS1 and C57BL/6 mice	↓Aβ plaques	[^Citation156]
	Donepezil	Liposome	In vivo: male Wistar rats	↑brain bioavailability	[^Citation154]
	Rivastigmine	Liposome	In vivo: male Wistar albino rats	↑memory recovery, ↓metabolic abnormalities	[^Citation152]
		SLN	In vitro: Franz diffusion cell	↑diffusion and not affect nasociliary disruption or cell necrosis	[^Citation153]
	Tarenflurbil	NPs/SLN	In vitro: brain cells	↑brain biodistribution pattern, ↑ the pharmacokinetic behavior	[^Citation160]
	Estradiol	PLGA	In vivo: male Sprague–Dawley	↑brain estradiol levels	[^Citation158]
	Galantamine hydrobromide	SLN	In vitro/ in vivo: male New Zealand rabbits	↑substantial memory restoration potential, ↑bioavailability	[^Citation155]
	bFGF	STL-PEG-PLGA	In vivo: male Sprague-Dawley rats	↓neuronal degeneration, ↓learning impairments, ↑direct transport of bFGF into the rat brain, ↓peripheral adverse reactions	[^Citation162]
PD	Phytochemicals Nanoformulations
	Resveratrol	NPs	In vitro/ in vivo: male albino Wistar rats	↑resveratrol blood levels for a more extended period, ↑bioavailability, ↑ pharmacological impact	[^Citation164]
		Lips@Fe3O4	In vitro/ In vivo: male Sprague-Dawley rats	↑sustained and delayed drug release, ↑efficiently penetrate the BBB, ↑drug concentration at the targeted area in the presence of an external magnetic field	[^Citation165]
		Vitamin E loaded resveratrol NEs	In vitro: brain cells	↓degenerative alterations, ↑antioxidant effect of resveratrol against hydrogen peroxide	[^Citation166]
		PS80-coated poly lactide NPs	Ex vivo: C57BL/6 mice	↑resveratrol concentration in the brain	[^Citation167]
	Curcumin and piperine	GMO-NPs	In vitro: rat PC12 cell line	↓αS protein oligomerization and fibril formation, ↓rotenone-induced toxicity, ↓GSH depletion induced by rotenone, ↓ration of Bcl-2/Bax, ↑autophagic pathway	[^Citation168]
			In vivo: male Balb/c mice and male C57BL/6 mice	↑cross the BBB, ↓rotenone-induced motor coordination impairment, ↓dopaminergic neuronal degeneration	[^Citation168]
	Naringenin	Vitamin E loaded NEs	In vitro/in vivo: Wistar rats	↑muscular coordination, grip strength, ↑swimming activity, ↑naringenin in the brain, ↑ bioavailability, ↑GSH, ↑ SOD, ↓MDA	[^Citation169]
	Gallic acid	PEI-HAS-NPs	In vitro: PC-12 cells	↓αSN aggregating, ↓hazardous oligomers.	[^Citation186]
	Nanoformulations of Synthetic Drugs
	Levodopa	NPs	In vitro/ in vivo	↓dyskinesia	[^Citation172]
	Bromocriptine	SLN based on a tristearin/tricaprin	In vitro	Controlled drug release by surrounding solid lipid barrier, firmly contained during the extended time established	[^Citation174]
		Chitosan	In vivo: Swiss albino mice	↑absorption in the brain and protects catalepsy and akinesia	[^Citation171]
	Ropinirole	PLGA	In vitro/ in vivo: male Wistar rats	↓neurodegeneration	[^Citation175]
		PLN	In vitro/in vivo: male albino mice	↓dose and dosing frequency, optimizing the therapeutic index, ↓side effects	[^Citation177]
	Selegiline	NEs	In vitro: neuro-2a neuroblastoma cell line	↑GSH, ↑SOD, ↓TBARS ↑drug bioavailability, ↑brain uptake, ↓decreased dopamine depletion	[^Citation181]
		NEs	In vivo: Wistar rats	↓neurodamage caused by free radicals, ↓subsequent metabolic alterations	[^Citation182]
	Apomorphine	SLNs	In vivo: male Wistar albino rats	↑oral bioavailability, ↓dose, and frequency of administration, effectively targeted apomorphine to the brain striatum	[^Citation180]
	Pentamidine	Chitosan coated niosomes	In vivo: male C57Bl/6 J mice	↓neuroinflammation, ↑dopaminergic neuronal function via blocking effect on glial-derived S100B function	[^Citation183]
	Pramipexole	Chitosan	In vivo: male Sprague-Dawley rats	Controlling motor deficits via its antioxidant potential, ↑SOD, ↑CAT, ↑ dopamine level in the brain	[^Citation178]

Abbreviations: ↑, increase or upregulation; ↓, decrease or downregulation; ASDs, amorphous solid dispersions; αSN, α-synuclein; APP, amyloid precursor protein; BACE, β-secretase; BDNF, brain-derived neurotrophic factor; bFGF, basic fibroblast growth factor; CAT, catalase; EGCG, epigallocatechin 3-gallate; MWCNTs, multiwalled carbon nanotubes; Lf-TMC NPs, lactoferrin-conjugated N-trimethylated chitosan nanoparticles; GMO, glyceryl monooleate; GSH, glutathione; iNOS, intrinsic nitric oxide synthase; lips@Fe3O4, Fe3O4 modified liposomes; MDA, malondialdehyde; MSCs, mesenchymal stem cells; NEs, nano emulsions; PS80-coated poly lactide NPs, polysorbate 80 coated poly(lactide) nanoparticles; NLCs, nanostructured lipid carriers; NP, nanoparticles; NPQ, nanoencapsulated quercetin; NSC, endogenous neural stem cells; PEI-HAS-NPs, polyethyleneimine-coated human serum albumin; PLGA-NPs, poly(lactide-co-glycolide nanoparticles; PLGA-PEG-B6, poly(lactide-co-glycolide)-block-poly(ethylene glycol)) conjugated with B6 peptide; SLNs, solid lipid nanoparticles; ROS, reactive oxygen species; SOD, superoxide dismutase; STL-PEG-PLGA, Solanum tuberosum lectin coupled polyethylene glycol-polylactide-polyglycolide.

Table 2 Phytochemical/Synthetic Nanoformulations Against ALS and Stroke

Disease	Component	Nano Vehicle/Method	Study Types	Results	References
ALS	Phytochemicals Nanoformulations
	Curcumin	NPs	In vitro: MSCs	Without cytotoxicity	[^Citation189]
		NPs	In vitro: human monocytic THP-1 cell	↓SOD1, ↑water solubility	[^Citation188]
		Nanomicelles	Clinical trial	↑safety, ↓serious adverse effects	[^Citation23]
	Nanoformulations of Synthetics Drugs
	FM19G11	Gold	In vitro: epSPCs	↑self-renewal, ↑PI3K/Akt and UCP2 and proliferation of epSPCs	[^Citation194]
	Riluzole	Liposome	In vitro: mouse brain endothelial bEND.3 and astrocyte C8D1A cells	↑uptake of riluzole in BBB cell model, ↑ TNF-α or H2O2	[^Citation191]
Stroke	Phytochemicals Nanoformulations
	Resveratrol	NPs	In vivo: male Sprague-Dawley rats	↓oxidative stress, ↓MDA, ↓brain edema, ↓apoptosis, ↓Bax and caspase-3, ↑neurogenesis, ↑BDNF expression.	[^Citation196]
	Curcumin	SLNs	In vivo: male Wistar rats	↑circulation duration, ↑SOD, ↑CAT, ↑GSH, ↑mitochondrial complex enzyme activity, ↓lipid peroxidation, ↓nitrite, ↓ acetylcholinesterase	[^Citation197]
	Quercetin	Nanoencapsulated	In vivo: male Sprague Dawley rats	↓iNOS, ↓caspase-3, ↓loss of pyramidal neurons	[^Citation198]
		Polymeric nanocapsules	In vivo: male Wistar rats	↑brain uptake, impressive mitochondrial localization, protecting mitochondrial structural and functional integrity via sequestering ROS, ↑GSH level, SOD and CAT activities	[^Citation199]
	Panax notoginsenoside	HLV	In vivo: male Sprague Dawley rats	↑bioactivity, ↓brain water content, ↓infarction volume, ↑ SOD, ↓LDH, H2O2, MDA	[^Citation200]
	Naringenin	Gel-c-PCL	In vitro: MSCs	↑release pattern, ↓TNF-α, IL-1β, COX2 and iNOS) via ↓NF-κB	[^Citation201]
	Retinoic Acid	NPs	In vitro: Murine N9 microglia; Organotypic hippocampal slices culture	↓microglia activation, ↓NO and the expression of iNOS, promoted arginase-1 and IL-4	[^Citation25]
	Nanoformulations of Synthetic Drugs
	rtPA	PEG-PCL	In vivo: Sprague Dawley rats	↓infarct volume, ↓neurological impairment, ↑half-life that is about 18 time greater than free rtPA	[^Citation202]
	Fasudil	Liposomal	In vivo: male Sprague-Dawley rats	↓tPA-derived cerebral hemorrhage, ↑TTW of thrombolytic therapy with tPA	[^Citation203]
	VEGF and Ang-1	HA–PLGA	In vitro: HUAECs/primary NSCs; in vivo: C57BL/6J rats	↑angiogenesis in the ischemic area, ↑ vascularization and axonal development.	[^Citation207]
	VEGF	Tf-PLs	In vivo: male Sprague-Dawley rats	↑brain-specific VEGF production, ↑neuroprotection via reducing cerebral infarcts, ↑neovascularization	[^Citation208]

Abbreviations: ↑, increase or upregulation; ↓, decrease or downregulation; Akt, protein kinase B; BDNF, brain-derived neurotrophic factor; bFGF, basic fibroblast growth factor; CAT, catalase; COX2, cyclooxygenase-2; GSH, glutathione; H2O2, hydrogen peroxide; HA–PLGA, hyaluronic acid poly(lactic-co-glycolic acid); HLV, hybrid liposomal vesicle; gel-c-PCL NPs, gelatin-coated polycaprolactone nanoparticles; IL-1β, Interleukin; iNOS, nitric oxide synthase; INVITE MC, curcumin loaded micelles; LDH, lactate dehydrogenase; MDA, Malondialdehyde; MSCs, mesenchymal stem cells; NEs, nano emulsions; PS80-coated poly lactide NPs, polysorbate 80 coated poly(lactide) nanoparticles; NF-kβ, nuclear factor-kβ; NLCs, nanostructured lipid carriers; NO, nitric oxide; NP, nanoparticles; NSC, endogenous neural stem cells; PI3K, phosphatidylinositol 3-kinase; SLNs, solid lipid nanoparticles; ROS, reactive oxygen species; SOD, superoxide dismutase; Tf-PLs, transferrin-coupled liposomes; TNF-α, Tumor necrosis factor; tPA, tissue-type plasminogen activator; VEGF, vascular endothelial growth factor; UCP2, mitochondrial uncoupling protein.

Figure 3 The potential uses of phytochemical/synthetic nanoformulations against multiple neurodegenerative diseases.

Abbreviations: AD, Alzheimer’s disease; ALS, Amyotrophic lateral sclerosis; bFGF, fibroblast growth factor; EPO, erythropoietin; DMF, dimethyl fumarate; EGCG, epigallocatechin 3-gallate; GA, Gallic acid; NPs, nanoparticles; PD, Parkinson’s disease; RA, rosmarinic acid; rtPA, recombinant tissue plasminogen activator.

Table 3 Phytochemical/Synthetic Nanoformulations in Combating HD and MS

Disease	Component	Nano Vehicle/Method	Study Types	Results	References
HD	Phytochemicals Nanoformulations
	Curcumin	SLN	In vivo: female Wistar Rats	↑bioavailability, ↑GSH, ↑SOD	[^Citation211]
	Rosmarinic acid	SLN	In vitro/in vivo: Wistar rat	↓3-NP-induced impairments, ↓oxidative stress through ↑GSH and CAT, ↑brain medication concentration	[^Citation213]
MS	Nanoformulations of Synthetics Drugs
	Dimethyl fumarate	Nanocarriers	In vivo: Laca mice	↓dosage frequency	[^Citation215]
		SLN	In vitro: SH-SY5Y cells; In vivo: Wistar rats	↑bioavailability, ↑biological residence, ↑brain absorption	[^Citation216]
		SLN	In vitro: mouse brain microvascular endothelial cells; In vivo: Male, athymic mice	↑permeability values and brain absorption	[^Citation217]

Abbreviations: ↑, increase or upregulation; ↓, decrease or downregulation; 3-NP, 3-nitropropionic-acid; CAT, catalase; GSH, glutathione; HD, Huntington’s disease; MS, multiple sclerosis; NP, nanoparticles; SLNs, solid lipid nanoparticles; SOD, superoxide dismutase.

Figure 4 Nanophytochemicals and nanosynthetic drugs pave the road in combating neurodegenerative diseases, targeting different dysregulated mechanisms.

Abbreviations: AD, Alzheimer’s disease; ALS, Amyotrophic lateral sclerosis; NEs, nanoemulsions; NPs, nanoparticles; PD, Parkinson’s disease; PEG, polyethylene glycol; SLNs, solid lipid nanoparticles.

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