Table 2.

The indirect neurotoxicity of doxorubicin on chemo-brain.

	Mechanism	Interpretation	Ref
Indirect Neurotoxicity	Induction of oxidative Stress	Excess ROS production leads to the oxidative modification of biochemical molecules such as proteins, lipids, and nucleic acids.	Birben E et al. (72)
		ROS can activate NF-κB.	Herb M et al. (73)
			Yan S et al. (74)
	Inflammation	TNF-α can affect the volume of the hippocampus.	Kwatra M et al. (39)
		TNF-α can inhibit the long-term enhancing effects of hippocampal CA1 and the dentate gyrus.	Motaghinejad M et al. (75)
		TNF-α can augment the inflammatory signals by activating astrocytes and microglia, which lead to the local production of TNF-α in the brain.	Guidotti G et al. (76)
			Zhou H et al. (77)
		Binding of TNF-α to TNFR recruits intracellular proteins and transduces inflammatory signaling, leading to NF-κB translocates to the nucleus.	Mohamed RH et al. (78)
			Wu YQ et al. (79)
		activation of microglia and astrocytes via TNFR1 can enhance the expression and activity of NOX, particularly NOX2, leading to an increase in ROS production.	Blaser H et al. (80)
Indirect Neurotoxicity	Nitrification Stress	the nitrated MnSOD resulted in impaired mitochondrial respiratory activity, which in turn synergized with O2•− production.	Tangpong J et al. (30)
			Holley et al. (81)
	Apolipoprotein A-I	ApoA-1 exerts anti-inflammatory effects by blocking contact between activated T lymphocytes and monocytes and inhibiting the production of TNF-α.	Ronkina N et al. (82)
		ApoA-1 is sensitive to the doxorubicin-induced oxidative damage, leading to dyslipidemia and increased circulating TNF-α.	Ramalingayya GV et al. (22)
			Aluise CD et al. (70)
			Tangpong J et al. (83)

NF-κB, nuclear factor-κB; TNFR, TNF-α receptor; TNFR1, TNF-α receptor 1; NOX, NADPH oxidases; MnSOD:manganese superoxide dismutase; ApoA-1, Apolipoprotein A-I.