Antiglycoxidative properties of amantadine – a systematic review and comprehensive in vitro study

Figures & data

Figure 1. Chemical formula of amantadine.

Table 1. Inclusion and exclusion criteria.

Inclusion criteria	Exclusion criteria
Publications only in English	Publications in other languages
Articles describing the antiglycoxidative activity of amantadine	Articles not describing the antiglycoxidative activity of amantadine
Results collected during human research and also experimental in vivo and in vitro studies	Surveys, review articles, as well as case reports

Figure 2. Flow diagram of systematic review methodology (Prisma).

Table 2. Multidirectional properties of amantadine in clinical and experimental studies.

Study design	Endpoints	References
In vitro studies
Cells derived from rat livers (cytochrome P450 system) and whole blood treated with amantadine solutions (1-1000 μm)	Amantadine decreased lipid peroxidation and whole blood chemiluminescence, but only in 1000 μM	^35
Hypoxanthine/xanthine oxidase (HX/XO) superoxide generating system	Amantadine scavenged HO• and O2•^-	^38
2-Deoxyribose and dopamine-liberating neurons treated with amantadine solutions (0.05–1.0 mm)	Amantadine prevented oxidative stress-induced damage to neurons, generating 2-deoxyribose and dopamine	^38
Primary cultures (different composition of neurons, microglia, and astroglia) of rat mesencephalon pre-treated with amantadine solution (30 µm) and treated with lipopolysaccharides (LPS) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (dopaminergic neurotoxins)	Amantadine showed a protective impact of LPS and MPTP toxicity for rat midbrain cultures by inhibiting the release of proinflammatory factors in microglia, enhancing the astroglial expression of a glial-derived neurotrophic factor (GNDF), and also alleviating activation of Phox	^36
In vitro ROS scavenging in the neutrophil respiratory burst, hydrogen donating and stabilising DPPH, ABTS•^+ scavenging, as well as ferric reducing antioxidant power (FRAP) of amantadine solutions	Amantadine did not show in vitro antioxidant capacity in any assay	^75
In vitro DPPH radical scavenging capacity of amantadine and rasagiline solutions (200–1000 µg/mL)	At lower concentrations (200–400 µg/mL), there was a definite difference between amantadine and rasagiline, with amantadine showing more intense antioxidant activity than rasagiline; at higher doses (600–1000 µg/mL), antioxidant and radical scavenging activities of both drugs were comparable; the experiment proved the intrinsic activity of rasagiline and amantadine, which may alleviate the oxidative stress pathways	^37
In vivo studies
Wistar albino rats treated with amantadine (2 mg/mL, twice/day) for a week, a month, or three months; total thiols and malondialdehyde concentrations in rat corneas measured	Amantadine did not change the median levels of total thiols and malondialdehyde in comparison to the control group	^76
6-Hydroxydopamine (6-OHDA)-induced parkinsonism Wistar albino rat model; animals treated with spirulina (500 mg/kg, once or twice/day) or a combination of spirulina (500 mg/kg, once/day) with amantadine (20 mg/kg, once/day) for 30 days before and 14 days after 6-OHDA injection; post-lesion produced rotational behaviour measurement at two-week intervals (37th and 44th day); locomotors activity assayed on 44th day; muscle coordination assessed on 48th day; antioxidant tests (thiobarbituric acid reactive substances [TBARS] and [GSH]), as well as dopamine level determined on 49th day	Both body rotations (ipsilateral and contralateral) were significantly decreased after treatment with spirulina (twice/day); a higher percentage of improvement was shown in the reduction of both body rotations in the animals administered spirulina + amantadine; body movements and locomotor activity were improved in spirulina + amantadine- and spirulina-treated-twice/day group; similar results were also seen in antioxidant levels which later reached the normal value; the dopamine contents increased only in spirulina + amantadine group	^39
Spinal cord injury (SCI) Sprague–Dawley rat model treated with amantadine (45 mg/kg/day) for a week; oxidative stress (malondialdehyde and GSH level, as well as myeloperoxidase (MPO) activity), inflammation, and angiogenesis parameters assessed	Amantadine reduces oxidative stress, inflammation, as well as apoptosis and alleviates spinal SCI by inducing angiogenesis	^40
White rat model of severe traumatic brain injury (TBI) treated with amantadine (5 mg/kg), ademol (2 mL/kg), or 0.9% NaCl solution (2 mL/kg); brain oxidative stress parameters determined	Amantadine significantly reduced lipid peroxidation and oxidative degradation of proteins, as well as enhanced antioxidant enzymes concentration in a damaged brain, thus, it is relevantly more effective compared to 0.9% NaCl solution, but significantly less efficiently in comparison with ademol	^41
32 patients suffering from TBI of whom 18 treated with amantadine in an open clinical trial	Amantadine-treated patients showed decreased malondialdehyde concentration, increased β-carotene level, and longer survival after only one week of therapy	^42

Note: DPPH: 2,2-diphenyl-1-picrylhydrazyl; FRAP: ferric reducing antioxidant power; GNDF: glial-derived neurotrophic factor; GSH: reduced glutathione; HO•: hydroxyl radical; HX/XO: hypoxanthine/xanthine oxidase; LPS: lipopolysaccharides; MPO: myeloperoxidase; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; O₂•^-: superoxide anion; ROS: reactive oxygen species; SCI: spinal cord injury; TBARS: thiobarbituric acid reactive substances; TBI: traumatic brain injury; 6-OHDA: 6-hydroxydopamine.

Figure 3. The influence of amantadine and other additives on scavenging of ROS and total antioxidant potential. AA: ascorbic acid; ALA: α-lipoic acid; DPPH: 2,2-diphenyl-1-picrylhydrazyl radical scavenging capacity; H₂O₂: hydrogen peroxide scavenging; HO•: hydroxyl radical scavenging; NAC: N-acetylcysteine; TAC: total antioxidant capacity; TOS: total oxidant status; ∗p < 0.05 versus control (amantadine); ∗∗p < 0.01 versus control (amantadine); ∗∗∗p < 0.001 versus control (amantadine).

Figure 4. The influence of amantadine and other additives on protein glycoxidation products in various models. AA: ascorbic acid; ALA: α-lipoic acid; BSA: bovine serum albumin; ChT: chloramine T-induced albumin oxidation; DT: dityrosine; Fru: fructose-induced albumin glycation; Gal: galactose-induced albumin glycation; Glc: glucose-induced albumin glycation; GO: glyoxal-induced albumin glycation; KN: kynurenine; MGO: methylglyoxal-induced albumin glycation; NAC: N-acetylcysteine; NFK: N-formylkynurenine; TRY: tryptophan; ∗p < 0.05 versus positive control (glycation/oxidising agent); ∗∗p < 0.01 versus positive control (glycation/oxidising agent); ∗∗∗p < 0.001 versus positive control (glycation/oxidising agent); ^#p < 0.05 versus negative control (BSA); ^##p < 0.01 versus negative control (BSA); ^###p < 0.001 versus negative control (BSA).

Figure 5. The influence of amantadine and other additives on protein glycation products in various models. AA: ascorbic acid; AGE: advanced glycation end products; ALA: α-lipoic acid; AP: Amadori products; BSA: bovine serum albumin; βA: β-amyloid; ChT: chloramine T-induced albumin oxidation; Fru: fructose-induced albumin glycation; Gal: galactose-induced albumin glycation; Glc: glucose-induced albumin glycation; GO: glyoxal-induced albumin glycation; MGO: methylglyoxal-induced albumin glycation; NAC: N-acetylcysteine; ∗p < 0.05 versus positive control (glycation/oxidising agent); ∗∗p < 0.01 versus positive control (glycation/oxidising agent); ∗∗∗p < 0.001 versus positive control (glycation/oxidising agent); ^#p < 0.05 versus negative control (BSA); ^##p < 0.01 versus negative control (BSA); ^###p < 0.001 versus negative control (BSA).

Figure 6. The influence of amantadine and other additives on protein oxidation products in various models. AA: ascorbic acid; ALA: α-lipoic acid; AOPP: advanced oxidation protein products; BSA: bovine serum albumin; ChT: chloramine T-induced albumin oxidation; Fru: fructose-induced albumin glycation; Gal: galactose-induced albumin glycation; Glc: glucose-induced albumin glycation; GO: glyoxal-induced albumin glycation; MGO: methylglyoxal-induced albumin glycation; NAC: N-acetylcysteine; PC: protein carbonyls; ∗p < 0.05 versus positive control (glycation/oxidising agent); ∗∗p < 0.01 versus positive control (glycation/oxidising agent); ∗∗∗p < 0.001 versus positive control (glycation/oxidising agent); ^#p < 0.05 versus negative control (BSA); ^##p < 0.01 versus negative control (BSA); ^###p < 0.001 versus negative control (BSA).

Figure 7. Visualisation of an amantadine docking site (mode 1) in BSA.

Table 3. The results of a molecular docking simulation of amantadine to BSA.

Mode	Affinity (kcal/mol)	RMSD (lower bond)	RMSD (upper bond)	Amino acid residues
1	−6.4	0.000	0.000
2	−6.4	0.023	2.271
3	−6.4	0.130	2.297
4	−6.4	1.455	2.999
5	−5.6	33.261	34.494	TYR-160
6	−5.6	33.245	34.455	TYR-160
7	−5.6	33.257	34.513
8	−5.6	33.528	34.787	LEU-115
9	−5.6	33.514	34.765	LEU-115

Note: LEU: leucine; RMSD: root-mean-square deviations of atomic positions; TYR: tyrosine.

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Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request. Some data may not be made available because of privacy or ethical restrictions.