Abstract：OBJECTIVE To investigate the neuroprotective effects of HDAC6 inhibitor tubastatin A on cisplatin-induced cognitive impairment in mice. METHODS Male C57BL/6 mice were randomly assigned into normal control group, model group, model+tubastatin A group, and tubastatin A group. The mice model of chemo brain was established by intraperitoneal injections with cisplatin for 3 cycles consisting of 5 daily injections followed by a 5-day rest with no injection. Tubastatin A (25 mg·kg-1) was administered intraperitoneally 1 h before cisplatin injection. The ability of learning and memory was assessed by Morris water maze. The mitochondrial axonal transport was analyzed with immunofluorescence, using TOMM20, a mitochondrial marker protein. The brain mitochondrial function, including cytochrome c oxidase activity, mitochondrial ATP production, and mitochondrial membrane potential (MMP) measurements, were measured by biochemical assay. The α-tubulin acetylation level was detected by Western blot. The levels of pre-synaptic marker synapsin-1 and post-synaptic marker PSD95 were examined by immunofluorescence. RESULTS Compared with the control group, the retention of target quadrant was significantly reduced in the cisplatin group. Cisplatin-treated mice exhibited a significantly impaired mitochondrial function as indicated by decreased cytochrome C oxidase activity, ATP production, and MMP, and mitochondrial transport deficits as evidenced by an obvious increase in the ratio of TOMM20 immunoreactivity in the soma to that in the stratum radiatum in the brain as compared with the controls. The levels of synapsin-1 and PSD95 in CA1 region of the hippocampus were remarkably decreased in cisplatin-treated mice. However, tubastatin A treatment significantly increased the retention of target quadrant, attenuated mitochondrial transport deficits and mitochondrial dysfunction, increased the α-tubulin acetylation level, and rescued the synaptic injury in brains of cisplatin group. CONCLUSION No significant difference is observed in the cognition, mitochondrial function and synaptic proteins between the normal control group and tubastatin A group. Tubastatin A can alleviate mitochondrial transport disorder, mitochondrial dysfunction, and cisplatin-elicited decrease in synaptic proteins by increasing the level of a-tubulin acetylation, thereby improving cisplatin-induced learning and memory impairment in mice.
AHLES T A, SAYKIN A J. Candidate mechanisms for chemotherapy-induced cognitive changes[J]. Nat Rev Cancer, 2007, 7(3): 192-201.
[2]
KOPPEN C, REIFSCHNEIDER O, CASTANHEIRA I, et al. Quantitative imaging of platinum based on laser ablation-inductively coupled plasma-mass spectrometry to investigate toxic side effects of cisplatin[J]. Metallomics, 2015, 7(12): 1595-1603.
[3]
CORREA D D, HESS L M. Cognitive function and quality of life in ovarian cancer[J]. Gynecol Oncol, 2012, 124(3): 404-409.
[4]
GANA S A, RAMADOSS M, MAHADEVAN M. Histone deacetylase (HDAC) inhibitors-emerging roles in neuronal memory, learning, synaptic plasticity and neural regeneration[J]. Curr Neuropharmacol, 2016, 14(1): 55-71.
[5]
ZHANG L, LIU C, WU J, et al. Tubastatin A/ACY-1215 improves cognition in Alzheimer's disease transgenic mice[J]. J Alzheimers Dis, 2014, 41(4): 1193-1205.
[6]
DOMPIERRE J P, GODIN J D, CHARRIN B C, et al. Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington's disease by increasing tubulin acetylation[J]. J Neurosci, 2007, 27(13): 3571-3583.
[7]
WANG Z, LENG Y, WANG J, et al. Tubastatin A, an HDAC6 inhibitor, alleviates stroke-induced brain infarction and functional deficits: potential roles of alpha-tubulin acetylation and FGF-21 up-regulation[J]. Sci Rep UK, 2016, 6: 19626.
[8]
CHIU G S, MAJ M A, RIZVI S, et al. Pifithrin-mu prevents cisplatin-induced chemobrain by preserving neuronal mitochondrial function[J]. Cancer Res, 2017, 77(3): 742-752.
[9]
ZHOU W, KAVELAARS A, HEIJNEN C J. Metformin prevents cisplatin-induced cognitive impairment and brain damage in mice[J]. PLoS One, 2016, 11(3): e0151890.
[10]
GOVINDARAJAN N, RAO P, BURKHARDT S, et al. Reducing HDAC6 ameliorates cognitive deficits in a mouse model for Alzheimer's disease[J]. Embo Mol Med, 2013, 5(1): 52-63.
[11]
KAY K R, SMITH C,WRIGHT A K, et al. Studying synapses in human brain with array tomography and electron microscopy[J]. Nat Protoc, 2013, 8(7): 1366-1380.
[12]
DZAGNIDE A, KATSARAVA Z, MAKHALOVA J, et al. Repair capacity for platinum-DNA adducts determines the severity of cisplatin-induced peripheral neuropathy[J]. J Neurosci, 2007, 27(35): 9451-9457.
[13]
GIURGIOVICH A J, DIWAN B A, OLIVERO O A, et al. Elevated mitochondrial cisplatin-DNA adduct levels in rat tissues after transplacental cisplatin exposure[J]. Carcinogenesis, 1997, 18(1): 93-96.
[14]
YANG Z, SCHUMAKER L M, EGORIN M J, et al. Cisplatin preferentially binds mitochondrial DNA and voltage-dependent anion channel protein in the mitochondrial membrane of head and neck squamous cell carcinoma: possible role in apoptosis[J]. Clin Cancer Res, 2006, 12(19): 5817-5825.
[15]
MARTINS N M, SANTOS N A, CURTI C, et al. Cisplatin induces mitochondrial oxidative stress with resultant energetic metabolism impairment, membrane rigidification and apoptosis in rat liver[J]. J Appl Toxicol, 2008, 28 (3): 337-344.
[16]
ZSENGELLER Z K, ELLEZIAN L, BROWN D, et al. Cisplatin nephrotoxicity involves mitochondrial injury with impaired tubular mitochondrial enzyme activity[J]. J Histoche Cytochem, 2012, 60(7): 521-529.
[17]
PODRATZ J L, KNIGHT A M, TA L E, et al. Cisplatin induced mitochondrial DNA damage in dorsal root ganglion neurons[J]. Neurobiol Dis, 2011, 41(3): 661-668.
[18]
LOMELI N, DI K, CZERNIAWSKI J, et al. Cisplatin-induced mitochondrial dysfunction is associated with impaired cognitive function in rats[J]. Free Radical Bio Med, 2017, 102: 274-286.
[19]
HUBBERT C, GUARIDIOLA A, SHAO R, et al. HDAC6 is a microtubule-associated deacetylase[J]. Nature, 2002, 417(6887): 455-458.
[20]
GUO W, NAUJOCK M, FUMAGALLI L, et al. HDAC6 inhibition reverses axonal transport defects in motor neurons derived from FUS-ALS patients[J]. Nat Commun, 2017, 8(1): 861.
[21]
GUEDES-DIAS P, SOARES T R, PINHO B R, et al. HDAC6 inhibition induces mitochondrial fusion, autophagic flux and reduces diffuse mutant huntingtin in striatal neurons[J]. BBA, 2015, 1852 (11): 2484-2493.
[22]
HOLLENBECK P J. The axonal transport of mitochondria[J]. J Cell Sci, 2005, 118 (Pt 23): 5411-5419.
[23]
LIU X A, RIZZO V, PUTHANVEETTIL S V. Pathologies of axonal transport in neurodegenerative diseases[J]. Transl Neurosci, 2012, 3 (4): 355-372.
2021, Vol. 56 
