An investigation of the effect of thiamine pyrophosphate on cisplatin-induced oxidative stress and DNA damage in rat brain tissue compared with thiamine

Abstract

This study investigated the effects of thiamine pyrophosphate (TPP) at dosages of 10 and 20 mg/kg on oxidative stress induced in rat brain tissue with cisplatin and compared this with thiamine. Cisplatin neurotoxicity represents one of the main restrictions on the drug being given in effective doses. Oxidative stress is considered responsible for cisplatin toxicity. Our results showed that cisplatin increased the levels of oxidant parameters such as lipid peroxidation (thio barbituric acid reactive substance (TBARS)) and myeloperoxidase (MPO) in brain tissue and suppressed the effects of antioxidants such as total glutathione (GSH) and superoxide dismutase (SOD). TPP, especially at a dosage of 20 mg/kg, significantly reduced TBARS and MPO levels that increase with cisplatin administration compared with the thiamine group, while TPP significantly increases GSH and SOD levels. In addition, the level of 8-Gua (guanine), a product of DNA damage, was 1.7 ± 0.12 8-hydroxyl guanine (8-OH Gua)/105 Gua in brain tissue in the control group receiving cisplatin, compared with 0.97 ± 0.03 8-OH Gua/105 Gua in the thiamine pyrophosphate (20 mg/kg) group and 1.55 ± 0.11 8-OH Gua/105 Gua in the thiamine (20 mg/kg) group. These results show that thiamine pyrophosphate significantly prevents oxidative damage induced by cisplatin in brain tissue, while the protective effect of thiamine is insignificant.

Keywords

Cisplatin neurotoxicity rat thiamine oxidants

Introduction

Cisplatin (cis-diaminodichloroplatinum) was the first heavy metal used as an antineoplastic agent. It has been used to treat several kinds of solid tumors, including those of the lung, ovary, testis, bladder, head, neck, and endometrium.¹ Ototoxicity, neurotoxicity, and nephrotoxicity are dose-limiting side effects of cisplatin.² Neurotoxicity is a major reason why cisplatin is discontinued and the cumulative dosage limited, potentially reducing its chemotherapeutic efficacy.^3,4 Cisplatin exhibits preferential uptake in the dorsal root ganglia and produces a dose-dependent large fiber sensory neuropathy (neuronopathy).^1,5,6 Cultured rat embryo dorsal root ganglion models have been used to study the mechanisms of cisplatin neurotoxicity.⁷ Cisplatin has caused abnormalities in the nucleoli of spinal root ganglion cells of neurons. The mechanism involved thought to be related to platinum binding to DNA and interference with DNA synthesis.⁸ The hypothesis is that cisplatin-induced neuropathy may result from nuclear and nucleolar changes in the sensory ganglion cell body. After chronic cisplatin administration, the spinal ganglia and peripheral nerves showed severe damage to the spinal ganglia neurons, with predominant involvement of the nucleus and nucleolus associated with a decrease in cell size.^2,9 These changes described in rats also have been confirmed in mice.¹⁰ Oxidative stress is another significant mechanism in the pathogenesis of cisplatin-induced toxicity. Oxidative stress also plays a crucial role in neurotoxicity caused by various chemical substances, such as sodium fluoride.¹¹ Cisplatin is reported to produce a toxic effect in tissues by increasing free radical production and reducing that of antioxidants.^12,13 Increased oxygen radicals react with DNA to permit the formation of 8-hydroxy guanine (8-OH Gua), a product of damage to DNA.¹⁴ However, the neurotoxicity induced by cisplatin remains one of the main limitations on its use at the dosage desired. New research into cisplatin neurotoxicity is therefore continuing.

In this study, we aimed to investigate the effect of thiamine and its active metabolite thiamine pyrophosphate (TPP) in cisplatin-induced neurotoxicity. TPP emerges through the phosphatization of thiamine with thiamine phosphokinase in the liver. TPP is a cofactor for pyruvate dehydrogenase, transketolase, and α-ketoglutarate dehydrogenase enzyme, all of which play important roles in glucose metabolism. Thiamine increases nicotinamide adenine dinucleotide phosphate levels and antioxidant formation using the pentose phosphate pathway.¹⁵

To the best of our knowledge, no data or findings regarding the protective effect of TPP on cisplatin neurotoxicity have been reported in literature. Our study was intended as a biochemical investigation of the protective effects of TPP on cisplatin-induced neurotoxicity in rats and comparison of this effect with that of thiamine.

Materials and methods

Animals

A total of 42 male albino Wistar rats weighing 210–230 g were obtained from the Ataturk University Medicinal and Experimental Application and Research Center, Erzurum. Turkey. Animals were allowed 21 days to acclimatize before starting the experiments. They were maintained at a 12-h light and 12-h dark cycle (lights on 07: 00–19: 00 h) in air-conditioned constant temperature (22 ± 1°C) colony room, with free access to water and 20% (weight in weight) protein commercial chow. Animal experiments were performed in accordance with the National Guidelines for the Use and Care of Laboratory Animals and were approved by the local animal ethics committee of Ataturk University, Erzurum, Turkey (Ethics Committee Number: B.30.2.ATA.0.23.85-135; 90).

Chemical substances

Cisplatin CDDP vials (50 mg/100 ml; Cisplatin-Ebewe) were supplied by Liba Laboratories, Turkey; thiamine and TPP were provided by Biopharma, Russia; and thiopental sodium was obtained from IE Ulagay, Turkey. The chemicals 5,5′-dithiobis (2-nitrobenzoic acid; DTNB), heparin, nitro blue tetrazolium chloride, n-butanol: pyridine, reduced glutathione (GSH), ammonium acetate, trichloroacetic acid, and hydrogen peroxide (H₂O₂) were obtained from Sigma-Aldrich, Saint Louis, Missouri, USA, and thiobarbituric acid (TBA) from Merck KgaA, Germany.

Pharmacological procedures

The animals were randomly divided into six groups before the experimental procedures were initiated (thiamine 10 and 20 mg/kg groups, TPP 10 and 20 mg/kg groups, healthy animal group, and control group). Each group contained seven animals. All doses (in milligrams per kilogram) were administered intraperitoneally (i.p.). The four study groups were administered 10 or 20 mg/kg thiamine or TPP by the i.p. route.^16,17 The control group was administered distilled water as solvent. After 1 h of drug administration, these five animal groups were given cisplatin in a 5-mg/kg dose by the i.p. route once a day for 14 days. The healthy group was given distilled water once a day during that period. At the end of the study period, all the animals were killed with a high dose of anesthesia (50 mg/kg sodium thiopental). The doses used in this study are not equivalent to those used by humans because rats have different metabolic rates.¹⁸ Brains were extracted, the cerebrum was used after recovery of the upper layer, and biochemical examination was performed. The results from the thiamine and TPP groups were compared to those from the control and healthy groups.

Biochemical analysis of brain tissue

In this part, 0.2 mg of whole brain tissue was weighed for each brain. The samples were homogenized in ice with 2 mL buffers (consisting of 0.5% hexa desil tri methyl ammonium bromide (HDTMAB)), pH 6 potassium phosphate buffer for myeloperoxidase analyze, consisting of 1.15% potassium chloride (KCl) solution for thio barbituric acid reactive substance (TBARS) analysis, and phosphate buffer of pH 7.5 for the superoxide dismutase (SOD), and total glutathione (tGSH) analyses. Then, they were centrifuged at 4°C and 10,000 r/min for 15 min. The supernatant part was used as the analysis sample.

SOD analysis

Measurements were performed according to the method of Sun et al.¹⁹ When xanthine is converted into uric acid by xanthine oxidase, SOD forms. If nitro blue tetrazolium (NBT) is added to this reaction, SOD reacts with NBT and a purple-colored formazan dye is formed. The sample was weighed and homogenized in 2 ml of 20 mmol/L phosphate buffer containing 10 mmol/L ethylenediaminetetraacetic acid (EDTA) at pH 7.8. The sample was centrifuged at 6000 r/min for 10 min and then the obtained supernatant was used as the assay sample. The 2450 μL measurement mixture (0.3 mmol/L xanthine, 0.6 mmol/L EDTA, 150 μmol/L NBT, 0.4 mol/L sodium carbonate, and 1 g/L bovine serum albumin), 500 μL supernatant, and 50 μL xanthine oxidase (167 U/L) were vortexed. Then, it was incubated for 10 min. At the end of the reaction, formazan was formed. The absorbance of the purple-colored formazan was measured at 560 nm. As more of the enzyme exists, the least O₂ ⁻ radical that reacts with NBT is formed.

tGSH analysis

The amount of GSH in the total homogenate was measured according to the method of Sedlak and Lindsay, with some modifications.²⁰ The sample was weighed and homogenized in 2 mL of 50 mmol/L tris(hydroxymethyl)aminomethane-hydrogen chloride (tris–HCl) buffer containing 20 mmol/L EDTA and 0.2 mmol/L sucrose at pH 7.5. The homogenate was immediately precipitated with 0.1 mL of 25% trichloroacetic acid; the precipitate was removed after centrifugation at 4200 r/min for 40 min at 4°C, and the supernatant was used to determine GSH level. A total of 1500 μL of measurement buffer (200 mmol/L Tris–HCl buffer containing 0.2 mmol/L EDTA at pH 7.5), 500 μL supernatant, 100 μL DTNB (10 mmol/L), and 7900 μL methanol were added to a tube and vortexed and incubated for 30 min in 37°C.DTNB was used as a chromogen that formed a yellow-colored complex with sulfhydryl (SH) groups. The absorbance was measured at 412 nm using a spectrophotometer (Beckman DU 500, Global Medical Instrumentation Inc, Ramsey, Minnesota, USA). The standard curve was obtained using reduced GSH.

Determination of lipid peroxidation or MDA analysis

The concentrations of brain tissue lipid peroxidation were determined using the TBARS, a modified version of the method used by Nabavi et al.²¹ The rat brains were promptly excised and rinsed with cold saline. The brain tissue was scraped, weighed, and homogenized in 10 mL of 100 g/L KCl. The homogenate (0.5 mL) was added to a solution containing 0.2 mL of 80 g/L sodium lauryl sulfate, 1.5 mL of 200 g/L acetic acid, 1.5 mL of 8 g/L 2-thiobarbiturate, and 0.3 mL distilled water. The mixture was incubated at 98°C for 1 h. Upon cooling, 5 mL of n-butanol–pyridine (15:l) mixture was added. The mixture was vortexed for 1 min and centrifuged for 30 min at 4000 r/min. The absorbance of the supernatant was measured at 532 nm. The standard curve was obtained using 1,1,3,3-tetramethoxypropane. The results were expressed in nanomole malondialdehyde (MDA) equivalent per gram tissue.

MPO analysis

The activity of myeloperoxidase (MPO) in the total homogenate was measured according to the method of Wei and Frenkel, with some modifications.²² The sample was weighed and homogenized in 2 mL of 50 mmol/L phosphate buffer containing 0.5% HDTMAB and centrifuged at 3500 r/min for 60 min at 4°C. The supernatant was used to determine MPO activity using 1.3 mL 4-aminoantipyrine–2% phenol (25 mM) solution. Then, 25 mmol/L 4-aminoantipyrine–2% phenol solution and 0.0005% 1.5 mL H₂O₂ were added and equilibrated for 3–4 min. After establishing the basal rate, a 0.2-mL sample suspension was added and quickly mixed. Increases in absorbance at 510 nm for 4 min at 0.1-min intervals were recorded. Absorbance was measured at 412 nm using a spectrophotometer.

Isolation of DNA from brain tissue

Brain tissue was drawn and DNA isolated using Shigenaga et al.’s modified method.²³ Samples (50–200 mg) were homogenized at 4°C in 1 mL of homogenization buffer (0.1 mol/L sodium chloride (NaCl), 30 mmol/L Tris; pH 8.0, 10 mmol/L EDTA, 10 mmol/L 2-mercaptoethanol, 0.5% (volume per volume; v/v) Triton X-100) with six passes of a Teflon–glass homogenizer at 200 r/min. The samples were centrifuged at 4°C for 10 min at 1000g to pellet nuclei. The supernatant was discarded, and the crude nuclear pellet was resuspended and rehomogenized in 1 mL of extraction buffer (0.1 mol/L Tris; pH 8.0, 0.1 mol/L NaCl, 20 mmol/L EDTA) and recentrifuged as mentioned above for 2 min. The washed pellet was resuspended in 300 μL of extraction buffer with a wide orifice 200-μL Pipetman tip (Eppendorf, Germany). The resuspended pellet was subsequently incubated at 65°C for 1 h in the presence of 0.1 mL of 10% sodium dodecyl sulfate, 40 μL proteinase K, and 1.9 mL leukocyte lysis buffer. Afterward, ammonium acetate was added to the crude DNA sample to give a final concentration of 2.5 mol/L and centrifuged in a microcentrifuge for 5 min. The supernatant was removed and mixed with two volumes of ethanol to precipitate the DNA fraction. After centrifugation, the pellet was dried under reduced pressure and dissolved in sterile water. The absorbance of this fraction was measured at 260 and 280 nm. Purification of DNA was determined to be 1.8 at an absorbance A260/280 ratio.

DNA hydrolysis with formic acid

Approximately 50 mg of DNA was hydrolyzed with 0.5 mL of formic acid (60% v/v) for 45 min at 150°C.²⁴ The tubes were allowed to cool. The contents were then transferred to Pierce microvials (Sigma-Aldrich Corporation, Munich, Germany), covered with Kleenex tissues (Kimberly-Clark, Neenah, Wisconsin, USA), cut to size (secured in place using a rubber band), and cooled in liquid nitrogen. Formic acid was then removed by freeze-drying. Before analysis using high-performance liquid chromatography (HPLC), they were redissolved in the eluent (final volume 200 μL).^25,26

Measurement of 8-OH Gua with HPLC system

The amount of 8-OH Gua and Gua was measured using a HPLC system equipped with an electrochemical detector (HP Agilent 1100 module series, E.C.D. HP 1049 A, Agilent Technologies, Waldbronn, Germany), as described previously.^24,27 The amount of 8-OH Gua and Gua was analyzed on a 250 4.6-mm Supelco LC-18-S reverse-phase column. The mobile phase was 50 mM potassium phosphate, pH 5.5, with acetonitrile (97 volume acetonitrile and 3 volume potassium phosphate), and the flow rate was 1.0 mL/min. The detector potential was set at 0.80 V for measuring the oxidized base. Gua and 8-OH Gua (25 pmol) were used as standards. The 8-OH Gua levels were expressed as the number of 8-OH Gua molecules/105 Gua molecules.²⁸

Statistical analysis

All data were subjected to one-way analysis of variance using Statistical Package for Social Sciences 18.0 (Armonk, New York, USA) software. Differences among groups were obtained using the least significant difference option, and the significance was declared at p ≤ 0.0001. The results are expressed as mean ± SEM.

Results

The effects of TPP on SOD activity in brain tissue subjected to cisplatin neurotoxicity were reported; SOD activity was 3.8 ± 0.35 U/g (p < 0001 compared with the control group) in the group treated with 10 mg/kg TPP (p < 0.05 compared the control group) and 5.54 ± 0.21 nmol/g protein in the brain tissue of the group treated with 20 mg/kg TPP (p < 0.0001 compared with the control group), compared to 2.24 ± 0.18 U/g in the control group and 5.8 ± 0.24 U/g in the healthy animals (p < 0.0001 compared with the control group; Table 1).

Table 1.

Comparisons of groups in terms of oxidant and antioxidants parameters.^a

	N	SOD (U/g)	tGSH (nmol/g protein)	TBARS (nmol MDA eq/g tissue)	MPO (U/g)
Control	7	2.24 ± 0.18	1.4 ± 0.11	4.15 ± 0.13	3 ± 0.23
p Value		–	–	–	–
Healthy group	7	5.8 ± 0.24	3.38 ± 0.2	1.82 ± 0.1	1.41 ± 0.14
p Value		p < 0.0001^b	p < 0.0001^b	p < 0.0001^b	p < 0.0001^b
Thiamine 10 mg/kg group	7	2.77 ± 0.22	1.67 ± 0.21	3.81 ± 0.23	2.84 ± 0.33
p Value		p > 0.05	p > 0.05	p > 0.05	p > 0.05
Thiamine 20 mg/kg group	7	3.1 ± 0.59	1.92 ± 0.09	3.6 ± 0.36	2.48 ± 0.63
p Value		p > 0.05	p > 0.05	p > 0.05	p > 0.05
TPP 10 mg/kg group	7	3.8 ± 0.35	2.37 ± 0.19	2.68 ± 0.15	1.98 ± 0.08
p Value		p < 0.05	p < 0.001	p < 0.0001^b	p < 0.05
TPP 20 mg/kg group	7	5.54 ± 0.21	3.61 ± 0.23	1.44 ± 0.12	1.3 ± 0.13
p Value		p < 0.0001^b	p < 0.0001^b	p < 0.0001^b	p < 0.0001^b

SOD: superoxide dismutase; MDA: malondialdehyde; MPO: myeloperoxidase; tGSH: total glutathione; TPP: thiamine pyrophosphate; N: number of animals.

^a According to one-way analysis of variance, the activities of MPO and SOD levels of tGSH and TBARS of each groups versus control group were compared. All the values are expressed as mean ± SEM.

^b p ≤ 0.0001 was significant.

The effect of TPP on the tGSH level in brain tissue subjected to cisplatin neurotoxicity is shown in Table 1. The tGSH level was 2.37 ± 0.19 nmol/g protein in the brain tissue of the group treated with 10 mg/kg TPP (p < 0.001 compared with the control group), 3.61 ± 0.23 nmol/g protein in the brain tissue of the group treated with 20 mg/kg TPP (p < 0.0001 compared with the control group), 1.4 ± 0.11 in the control group subjected to cisplatin neurotoxicity, and 3.38 ± 0.2 in the healthy animal group (p < 0.0001 at 20 mg/kg TPP).

The effect of TPP on TBARS levels in brain tissue subjected to cisplatin neurotoxicity was reported; TBARS level in the brains of the rat group treated with 10 mg/kg TPP was 2.68 ± 0.15 nmol MDA eq/g tissue (p < 0.0001 compared with the control group). For 20 mg/kg, TPP was 1.44 ± 0.12 nmol MDA eq/g tissue (p < 0.0001 compared with the control group). The levels were 4.15 ± 0.13 and 1.82 ± 0.1 nmol MDA eq/g tissue, respectively, in the control group (p < 0.0001 compared with the control group; Table 1).

The effect of TPP on the MPO level in brain tissue subjected to cisplatin neurotoxicity is shown in Table 1; the MPO level was 1.98 ± 0.08 U/g protein in the brain tissue of the group treated with 10 mg/kg TPP (p < 0.05 compared with the control group), 1.3 ± 0.13 U/g protein in the brain tissue of the group treated with 20 mg/kg TPP (p < 0.0001 compared with the control group), 3 ± 0.23 in the control group subjected to cisplatin neurotoxicity and 1.41 ± 0.14 in the healthy group (p < 0.0001 at 20 mg/kg TPP).

The effect of TPP on 8-Hydroxy-2-deoxyguanine/Gua (effect on 8-OH Gua/Gua) in brain tissue subjected to cisplatin neurotoxicity was measured as a DNA damage product. In the group given 10 mg/kg TPP before cisplatin injection, the 8-OHGua/Gua level was 1.36 ± 0.11 pmol/L (p < 0.05 compared with the control group) and 0.97 ± 0.03 in the group given 20 mg/kg TPP (p < 0.0001 compared with the control group); the level was 1.7 ± 0.12 in the control group and 0.89 ± 0.02 pmol/L in the healthy group (p < 0.0001 compared with the control group; Table 2).

Table 2.

Comparisons of groups in terms of DNA damage products.^a

	N	DNA damage 8-OH Gua/105 Gua	p Value
Control group	7	1.7 ± 0.12	–
Healthy group	7	0.89 ± 0.02	p < 0.0001^b
Thiamine 10 mg/kg group	7	1.61 ± 0.1	p > 0.05
Thiamine 20 mg/kg group	7	1.55 ± 0.11	p > 0.05
TPP 10 mg/kg group	7	1.36 ± 0.11	p < 0.05
TPP 20 mg/kg group	7	0.97 ± 0.03	p < 0.0001^b

TPP: thiamine pyrophosphate; N: number of animals.

^a According to one-way analysis of variance, the product of DNA damage of each groups versus control group was compared. All the values are expressed as mean ± SEM.

^b p ≤ 0.0001 was significant.

The effect of thiamine on the SOD activity and tGSH, TBARS, MPO, and DNA damage level in brain tissue subjected to cisplatin neurotoxicity is shown in Tables 1 and 2. Based on these parameters, the effect of thiamine (10 and 20 mg/kg doses) is not significant in the controls (p > 0.05).

Discussion

This study investigated the protective effect of thiamine and TPP against cisplatin-induced neurotoxicity in rat brain tissue. Oxidative damage is a significant mechanism in the pathogenesis of toxicity caused by cisplatin, while cisplatin has been reported to establish a toxic effect in tissues by increasing free radical production and reducing antioxidant production.^12,13 Cisplatin and other chemotherapeutic agents cause lipid membrane peroxidation by increasing free oxygen radicals and cause extensive tissue damage.²⁹ Oxidative stress alters cell function and structure by affecting fat, carbohydrate, and protein synthesis and causing damage to DNA in biological systems.³⁰ Previous studies have shown that antioxidant replacement in animals given cisplatin reduces cisplatin associated auto-, nephro- and hematological toxicity.^29,31,32 Cisplatin was administered to all groups at a cumulative effect dosage such as to induce neurotoxicity (5 mg/kg). The neurotoxic effects were determined by measuring SOD tGSH, TBARS, MPO, and 8-OH Gua/105 Gua activities for each animal group. The activity and level, particularly in the 20 mg/kg TPP group, were very close to those of the healthy, nondrug group, and a significant neuroprotective effect against cisplatin-associated neurotoxicity was determined.

We observed significantly greater tissue TBARS, MPO, and DNA damage in the control group receiving cisplatin and a decline in tGSH levels and SOD activity, compared with the healthy animal group. Biochemical findings in the groups receiving thiamine at 10 and 20 mg/kg were almost identical to those in the negative control group; while in the 20 mg/kg TPP group, these parameters (SOD, TBARS, MPO, tGSH, and DNA damage) were almost the same as those in the healthy group. Oxidant parameters in the 20 mg/kg TPP group were statistically significantly lower compared with the 10 mg/kg TPP group, while antioxidants were higher. TBARS is one of the final products of lipid peroxidation. Elevated TBARS levels in tissue indicate that increased free oxygen radicals. The most important and harmful effect initiated in the cell by free radicals is lipid peroxidation.³³ TBARS causes more advanced destruction in cells.³⁴ The literature reports a high level of TBARS in injured tissues and low levels of MPO and tGSH.^35,36 TBARS, MPO, and tGSH results from the literature were obtained from injured and noninjured tissues. MPO is found in phagocytic cells (PNL). The enzyme MPO catalyzes the production of toxic hypochlorous acid from H₂O₂. PNLs produce excess quantities of the free oxygen radicals superoxide anion (O₂ ⁻) and hydroxyl radical (OH⁻) in an uncontrolled manner. Excess production of MPO and other reactive radicals leads to oxidative damage.^37,38 However, antioxidant defense mechanisms develop in the tissues against toxic oxygen radicals. In the event these defense mechanisms prove inadequate, serious tissue damage is caused.³⁹ tGSH levels in the brain tissue of the control group rats given cisplatin were much lower compared with those of the healthy animals. But TPP at a dosage of 20 mg/kg significantly prevented a decrease in brain tissue tGSH compared with the control group. tGSH is involved in several endogenous compound metabolic processes, such as estrogen, prostaglandin, and leukotrienes, in protecting cells against oxidative damage and toxic compounds.⁴⁰ tGSH, an antioxidant, enters into reactions with peroxides and free radicals and converts them into harmless products. Through this mechanism, tGSH protects the cells against oxidative damage by free radicals. tGSH maintains SH groups in reduced form in proteins and prevents their oxidization.⁴¹

Increased oxygen radicals react with DNA to produce 8-OHGua, a product of damage to DNA.¹⁴ Studies have also shown that cisplatin leads to DNA damage by binding to various proteins inside the cell.^42,43 A similar level of 8-OHGua was determined between the group given TPP, particularly at a dosage of 20 mg/kg, and the healthy group, compared with the controls.

TPP is a coenzyme in two-carbon unit transfer and in the catalysis of several enzymes, such as 2-oxoacid dehydrogenation (in decarboxylation and the conjugation of coenzyme A). Pyruvate dehydrogenase (PDH) plays a role in the synthesis of adenosine triphosphate, the main energy source of cell mitochondria. PDH plays a role in the central nervous system, in the synthesis of neurotransmitters and the acetylcholine needed for myelin production.⁴⁴

One study on rats showed that the phosphatase enzyme in Golgi bodies and granular endoplasmic reticulum originates from the lysosomes in fetal dorsal root ganglia. This effect of cisplatin, which has a distinct neurotoxic effect on dorsal root ganglia in which platinum accumulation is the highest, may be antagonized with the pyruvate dehydrogenase complex catalyzed with TPP replacement.^45

–48

In conclusion, we think that TPP, especially when administered in an appropriate dosage boosts the level of antioxidants against cisplatin-induced neurotoxicity. However, further studies are required on this subject.

Footnotes

Authors’ Note

Research was conducted in the university laboratory at Department of Pharmacology, Ataturk University, Erzurum, Turkey.

Conflict of Interest

All authors declared no conflicts of interest.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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