Pathogenic mechanisms and therapeutic promise of phytochemicals and nanocarriers based drug delivery against radiotherapy-induced neurotoxic manifestations

Figures & data

Figure 1. Manifestations and time course of radiotherapy-induced neurotoxic manifestations.

Table 1. The deleterious effect of radiotherapy in cognitive and hormonal dysfunction (1).

Injury type	Observation	Radiotherapy dose
Cognitive dysfunction	Cognitive dysfunction	25 Gy/single dose 10, 20 and 40 Gy/ single dose 20 Gy/4 dose and 40 Gy/8 dose
	Behavioral dysfunction and depression	6 Gy/single cycle 36 Gy/8 cycle
	Impaired auditory function, attention deficit syndrome, visual and verbal impairment	30–50 Gy
Motor dysfunction	Impairment un locomotion and grip strength	6 Gy/single cycle
Growth hormone alteration	Confirmed by arginine test and insulin tolerance test	50–60 Gy
Cellular and histological changes	Disruption of BBB	18 Gy
	Increased activation and proliferation of microglia	10 Gy
	Astrocytic hypertrophy	8 Gy
	Histological damage	15 Gy
	Enhanced vacuolation, damage to endoplasmic reticulum and mitochondria	2 *0.75 Gy
	Necrosis in hippocampus	2*10, 3*10 and 4*10
	Reduced maturation of neurons	2.5* (whole-body)
	Reduced density of endothelial cells and damage to BBB	0–50 Gy
	Gliosis, necrosis, and damaged BBB	50, 75, and 120 Gy
	Astrogliosis, BBB damage and astrogliosis	20–40 Gy
	Astrogliosis and cognitive dysfunction	40 Gy

Figure 2. Pathophysiological presentation of radiotherapy-induced neurotoxic manifestations.

Table 2. The role of various signaling molecules in ration induced brain damage.

Dose of radiotherapy	Mechanism involved	Signaling molecule involved	References
5–35 Gy/single cycle	Neuroinflammation	iNOS, COX-2, MCP-1IL-1β, ICAM-1, IL-6, MIP-2 and TNF-α,	(Kyrkanides et al., 2002)
10 Gy/single cycle		MCP-1, IL-1β and TNF-α	(Lee et al., 2010)
10 Gy/single cycle		COX-2, IL-1β, c-Jun, IL-6 and TNF-α	(Deng et al., 2012)
10 Gy/single cycle	Reduced neurogenesis	NG2, NeuN, GFAP and Ki-67 and Ki-67	(Monje et al., 2003)
2–10 Gy/single cycle		NG2, NeuN, DCX, GFAP and Ki-67 and CD68	(Rola et al., 2004)
10 Gy/single cycle	Increased oxidative stress	MDA	(Limoli et al., 2004)
1–10 Gy/single cycle		NOX-4, NF-kB, ROS and PAI-1	(Collins-Underwood et al., 2008)
10 Gy/single cycle 40 Gy/8 cycle	Increased extracellular matrix	TIMPs, MMPs and collagen type IV	(Lee et al., 2012)
10 Gy/single cycle	Reduced angiogenesis	VEGF, Tie-2, Ang 1 and 2	(Lee et al., 2011)
10 Gy/single cycle	Neuronal apoptosis / death of progenitor cells	AIF, p53, Caspase-3 and nitro tyrosine	(Pazzaglia et al., 2020)
2–10 Gy/single cycle		Annexin V and PARP	(Fukuda et al., 2005)

Figure 3. The neuroinflammatory aspect of radiotherapy.

Figure 4. The mechanism of neuroprotection by phytoconstituents.

Table 3. The neuroprotective role of various natural bioactive against radiotherapy-induced neurotoxic manifestations (132).

Phytoconstituents	Dose of radiotherapy	Dose of phytoconstituents	Mechanism of action
Quercetin	20 Gy	50 mg/kg for 15 days	Reduced neuroinflammation and exhibited antioxidant effect
	2 Gy	5–100 µM	Reduced ER stress, C/EBP-homologous protein (CHOP), and TNF-α level
Baicalein	16 Gy	10 mg/kg for 7 days	Inhibited neuronal apoptosis, death of stem progenitor cells, and stimulated neurogenesis
EGCG	3 Gy	2.5 and 5 mg/kg for 3 days	Reduced the level of TNF-α, IL-6, IL-1β, DNA damage, and inhibited apoptosis.
Cyanidin	6 Gy	50, 100 and 200 mg/kg for 14 days	Improved in body weight, complete bound, and inhibition of leucocytic proliferation
Silymarin	0.2-0.6 Gy	140 mg/kg/	Mitigated the DNA damage
Genistein	8.75 Gy	200 mg/kg	Reduced DNA damage and inhibition of leucocytic infiltration
Rutin	5 Gy	200 mg/kg for 21 days	Reduced the activity of GSK-3β, PI3K, Akt, and increased Nrf2 activity
5, 7-dihydroxyflavone	5 Gy	50 mg/kg for 21 days	Reduced the MDA, Aβ, and caspases

Table 4. The neuroprotective role of various extracts against radiotherapy-induced neurotoxic manifestations (132).

Extract	Active constituent	Dose of radiotherapy	Mechanism of action
Astragalus membranaceus	Astragalus and saponin.	4.5 Gy and 30 Gy	Reduction in lipid peroxidation, MDA level, and improvement in learning and memory
Salvia Miltiorrhiza	Tanshinone and cryptotanshinone	22 Gy	Reduction in oxidative stress, ICAM-1 and improvement in learning and memory
Broomrape	Ergosterin and cistanche	5 Gy	Reduction in oxidative stress, improvement in immune component, and increment in neuronal viability
Radix Hedysari	Hedysarum	2 Gy	Reduction in oxidative stress
safflower	Carthamin and safflower yellow	4 Gy	Reduction in oxidative stress
Arnebiae Radix	Shikonin and acetyl shikonin,	0.5 Gy	Reduction in oxidative stress and improvement in learning memory
Ginkgo	ginkgolides	20 Gy	Inhibition of apoptosis, stimulation of neurogenesis, reduction of ROS and neuronal cell death
Ginseng	Ginsenoside	30 Gy	Inhibition of apoptosis, stimulation of neurogenesis, and protection of hippocampal neuron
Shenqi	Codonopsis and astragalus polysaccharides	20 Gy	Reduced BBB permeability, reduced level of TNF-α, IL-1β, reduced expression of p53, and improved learning and memory
Renal invigoration (978-1)	Icariin and lignin	20 Gy	Inhibit apoptosis and improve learning memory

Figure 5. Showing the BBB permeation of nanocarriers in radiotherapy-induced neurotoxic manifestations.

Table 5. Phytoconstituents-based nanocarrier to manage radiotherapy-induced neurotoxic manifestations (192).

Phytoconstituents	Nanocarrier	Conjugation	Mechanism of neuroprotection
Coenzyme Q10	Polymeric nanocarriers	PEG-and tocopherol	Coenzyme Q10 nanocarriers enhanced the bioavailability and pharmacotherapy
Tanshinone IIA		PEG-PLA	Improved uptake into the brain via endocytosis
Rg3 and thioflavin T		Angiopep-2 and PLGA	Nanocarriers permeate the drug across BBB and mitigate the glial cells mediated neuroinflammation
Urocortin		Odorranalectin, PEG and PLGA	Mucoadhesivness improved the bioavailability of the brain and exhibited neuroprotection.
Piperine		Tripolyphosphate	A positively charged surface potentiated the mucoadhesiveness and showed the neuroprotective effect.
Huperzine A		lactoferrin	Positively charged surface and endocytosis increased the bioavailability in CNS
N-acetyl cysteine		PAMAM dendrimers	Increased cellular uptake, antioxidant and anti-inflammatory effects were responsible for neuroprotection.
Astaxanthin	Lipid-based nanocarriers	SLNs	Enhanced loading capacity and drug accumulation in neurons exhibited neuroprotection.
Curcumin		Lactoferrin	Increased permeation across BBB synergized neuroprotection
Curcumin derivative		Lactoferrin and ApoE	Lactoferrin and ApoE increased permeation across BBB synergized neuroprotection
Se	Inorgenic nanocarriers	B6 peptide	Increased uptake across and intrinsic antioxidant, as well as anti-inflammatory effects, were responsible for neuroprotection.
Anthocyanin		PEG	Increased uptake across and intrinsic antioxidant, as well as anti-inflammatory effects, were responsible for neuroprotection.
Osmotin		Dextran	Magnetic targeting overcome the pharmacokinetic limitations and increased neuroprotective effect
Berberine	Carbon nanocarriers	polysorbate 80	polysorbate 80 improved the biocompatibility and bioavailability, and pharmacotherapy
Gallic acid	Biomimetic nanocarriers	Exosomes	Exosomes improved the solubility, bioavailability, neuronal uptake, and neuroprotection

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