Effects of gastrodin on 5-HT and neurotrophic factor in the treatment of patients with post-stroke depression

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1 EXPERIMENTAL AND THERAPEUTIC MEDICINE 16: , 2018 Effects of gstrodin on 5-HT nd neurotrophic fctor in the tretment of ptients with post-stroke depression GANG LI 1, YUNXIA MA 1, JINMING JI 1, XINGYAN SI 2 nd QIJIANG FAN 1 Deprtments of 1 Neurology nd 2 Anesthesiology, Binzhou City Center Hospitl, Binzhou, Shndong , P.R. Chin Received September 5, 2017; Accepted September 3, 2018 DOI: /etm Abstrct. Effects of gstrodin on 5-HT nd neurotrophic fctor in the tretment of ptients with post-stroke depression (PSD) were investigted. A totl of 78 PSD ptients were selected in Binzhou City Center Hospitl from September 2013 to December Ptients were rndomly divided into the control group nd experimentl group, 39 ptients in ech group. Ptients in the control group were treted with conventionl drug fluoxertine hydrochloride for 2 months, nd ptients in the experimentl group were treted with gstrodin. The levels of 5-HT nd neurotrophic fctors in blood were mesured using the enzyme-linked immunosorbent ssy (ELISA) kit before, nd t 1 nd 2 months fter tretment. The Hmilton Depression Scle (HAMD), Activities of Dily Living (ADL) scle, NIH Stroke Scle/Score (NIHSS) nd Stroke Impct Scle (SIS) were used to evlute the efficcy of tretment. Tretment efficcy ws compred between the two groups. The levels of 5-HT nd neurotrophic fctors were significntly higher in the experimentl group thn those in the control group t 1 nd 2 months fter tretment (P<0.05), nd HAMD, ADL, NIHSS nd SIS scores were ll better in the experimentl group thn in the control group (P<0.05). In ddition, significntly less side effects were found in the experimentl group thn tht in the control group, nd tretment efficcy in the experimentl group ws significntly better thn tht in the control group (P<0.05). Gstrodin is effective in the tretment of PSD nd should be populrized. Introduction Post-stroke depression (PSD) is considered to be the most common nd severe mentl illness fter stroke. Approximtely one-third of stroke survivors suffer from severe depression, which cn dversely ffect ptient's cognitive function, Correspondence to: Dr Gng Li, Deprtment of Neurology, Binzhou City Center Hospitl, 108 Hungchengnn Rod, Huimin, Binzhou, Shndong , P.R. Chin E-mil: g584ed@163.com Key words: post-stroke depression, neurotrophic fctor, 5-HT, gstrodin functionl recovery, nd survivl. It is generlly believed tht the dmged neurl circuits of emotion regultion cused by stroke re the min cuse of PSD. Gstrodin is one of the mjor ctive extrcts of the root of Gstrodi elt Bl (1). Gstrodin is often used for nti-convulsions, nlgesi, sedtion, nd is lso used in the tretment of vertigo, prlysis nd other diseses. In ddition, studies hve shown tht gstrodin cn promote lerning nd memory bilities (2). Gstrodin hs lso been proven to be ble to protect corticl neurons nd strocytes from injury nd reduce ischemic-induced neuronl dmge (3,4). However, the clinicl effects of gstrodin on PSD hve not been well studied. As neurotrnsmitter, 5-HT is involved in the regultion of pin, sleep nd body temperture nd other physiologicl functions. The bnorml content nd function of 5-HT in the centrl nervous system my be ssocited with mentl illness, migrine nd other diseses (5). The neurotrophic fctor (BDNF) is brin-derived protein tht plys n importnt role in the survivl, differentition, growth nd development of neurons during the development of the centrl nervous system. Studies hve shown tht BDNF deficiency cn led to post-trumtic stress disorder, which is commonly known s phobi (6). The im of this study ws to investigte the effects of gstrodin on levels of 5-HT nd BDNF in PSD ptients nd to ssess the efficcy of gstrodin in the tretment of PSD. Ptients nd methods Clinicl dt. A totl of 78 ptients with PSD were selected from September 2013 to December 2016 in Binzhou City Center Hospitl (Binzhou, Chin). The ptients included 40 mles nd 38 femles, nd the ge rnged from 48 to 76 yers with n verge ge of 62.7±6.45 yers. This study ws pproved by the Ethics Committee of Binzhou City Center Hospitl. All the ptients signed n informed consent. Dignostic criteri for stroke. Stroke ws dignosed ccording to the 2014 edition of Guide to the dignosis nd tretment of cute cerebrl ischemic stroke in Chin (7): i) cute onset; ii) combined with systemic or focl neurologicl deficits; iii) neurologicl deficit signs nd symptoms lst longer thn hours; iv) trnscrnil CT nd mgnetic resonnce imging (MRI) of ischemic lesions re consistent with clinicl signs; nd v) exclusion of non-vsculr cerebrl hemorrhge nd brin lesions by brin CT nd MRI.

2 4494 LI et l: GASTRODIN IN POST-STROKE DEPRESSION Tble I. Comprison of the generl informtion between two groups. Items Control group (n=39) Experimentl group (n=39) χ 2 vlue P-vlue Age (yers) 65.10± ± Sex (mle) n (%) 21 (53.85%) 19 (48.72%) Stroke type n (%) Atherosclerosis 14 (35.90%) 13 (33.33%) Crdic embolism 11 (28.21%) 12 (30.77%) Lcunr infrction 13 (33.33%) 10 (25.64%) Other 1 (2.56%) 4 (10.26%) Course of PSD (dys) 22.51± ± Dignostic criteri for nxiety nd depression. Anxiety nd depression were dignosed ccording to the dignostic criteri described in the Chinese Mentl Disorder Clssifiction nd Dignosis Stndrds 3rd Edition proposed by the Chinese Medicl Assocition Psychitric Brnch (8): i) loss of plesure nd interest; ii) ftigue nd limited energy; iii) long-term low self-evlution; iv) reduced self-thinking bility, mnifested s mentl retrdtion or excitement; v) sleep disorder; vi) self injury nd motivtion; nd vii) libido, ppetite, nd body weight different from wht they used to be prior to PSD. Inclusion criteri. i) All ptients included in this study were cliniclly dignosed with stroke dignosis; ii) ptients without drug llergies; iii) ptients who hd no nxiety nd depression before stroke; nd iv) ptients who hd cler consciousness nd certin communiction skills. Exclusion criteri. i) ptients with nxiety nd depressive symptoms; ii) ptients with suicidl tendencies; iii) ptients with nervous system dysfunction nd pst severe hert, liver, nd kidney dysfunction; iv) ptients with history of drug llergies; v) ptients who were treted within 7 dys before dmission; nd vi) ptients unble to complete tretment. Tretment. The 78 ptients were rndomly divided into the control group (21 were mles nd 18 were femles) nd experimentl group (18 were mles nd 21 were femles), 39 cses in ech group. Ptients in the control group were treted with conventionl drug fluoxetine hydrochloride cpsules (Lilly Suzhou Phrmceuticl Group Co., Ltd., Suzhou, Chin; SFDA pprovl no. J ) with dose of 12.5 mg ech time nd 3 times per dy. Ptients in the control group were treted with gstrodin cpsules (KPC Phrmceuticls Inc., Kunming, Chin; SFDA pprovl no. H ) with dose of 25 mg ech time nd 3 times per dy. All ptients were treted for 2 months. Mesurement of indictors. Hmilton Depression (HAMD) scle, Activities of Dily Living (ADL) scle, NIH Stroke Scle/Score (NIHSS) nd Stroke Impct Scle (SIS) scoring were performed by the sme physicin before, nd t 1 nd 2 months fter tretment. Blood smples were collected from ech ptient before nd t 1 nd 2 months fter tretment. The levels of neurotrophic fctor (BDNF) nd 5-hydroxytryptmine (5-HT) were mesured using the BDNF ELISA kit (ct. no. 3765; R&D Systems, Inc., Minnepolis, MN, USA) nd 5-HT ELISA kit (ct. no. 4493; R&D Systems, Inc.). Side effects minly include systemic or locl llergies, gstrointestinl disorders (such s nuse, vomiting, dyspepsi, dirrhe nd dysphgi), norexi, dizziness, hedche, bnorml sleep, ftigue, mentl stte bnormlities, visul bnormlities, xeromycteri, dizziness nd stomch upset. Adverse effects were recorded. Totl effective rte (%) = (number of cured ptients + number of ptients showed prtil improvement)/totl number of ptients. Sttisticl nlysis. Dt were nlyzed by GrphPd Prism softwre (version 5.01). Mesurement dt were expressed s men ± SD. ANOVA ws used for comprison between multiple groups nd the post hoc test ws Dunnett's test. Percentge (%) ws used to express the enumertion dt nd Chi-squre test ws used for dt nlysis. P<0.05 ws considered to indicte sttisticlly significnt difference. Results Comprison of the generl informtion between the two groups of ptients. As shown in Tble I, no significnt differences in ge, sex, types of stroke nd course of PSD were found between the two groups (P>0.05). Comprison of 5-HT levels between the two groups before nd fter tretment. Before tretment, no significnt differences in the levels of 5-HT were found between the two groups (P>0.05). Compred with the preopertive levels, the 5-HT levels were significntly incresed in the two groups of ptients t 1 nd 2 months fter tretment (P<0.05). In ddition, the 5-HT levels were significntly higher in the experimentl group thn those in the control group t 1 nd 2 months fter tretment (P<0.05; Tble II). Comprison of BDNF levels between the two groups before nd fter tretment. No significnt differences in the levels of BDNF were found between the two groups before tretment (P>0.05). Compred with the preopertive levels, the BDNF levels were significntly incresed in the two groups of ptients t 1 nd 2 months fter tretment (P<0.05). In ddition, the levels of BDNF were significntly higher in the experimentl

3 EXPERIMENTAL AND THERAPEUTIC MEDICINE 16: , Tble II. Comprison of 5-HT levels between the two groups before nd fter tretment (men ± SD, ng/ml). 1 month fter 2 months fter Groups n Before tretment tretment tretment Control group ± ± ±14.05 b Experimentl group ± ±10.23 b,d ±12.83 c,d t vlue P-vlue P<0.05 compred with the preopertive level; b P<0.01 compred with the preopertive level; c P<0.001 compred with the preopertive level; d P<0.05 compred with the control group. Tble III. Comprison of BDNF levels between the two groups before nd fter tretment (men ± SD, ng/ml). 1 month fter 2 months fter Groups n Before tretment tretment tretment Control group ± ± ±3.62 b Experimentl group ± ±2.07,c 25.78±4.41 b,c t vlue P-vlue P<0.05 compred with the preopertive level; b P<0.01 compred with the preopertive level; c P<0.05 compred with the control group. Tble IV. Comprison of HAMD scores between the two groups of ptients before nd fter tretment (men ± SD). 1 month fter 2 months fter Groups n Before tretment tretment tretment Control group ± ± ±0.79 b Experimentl group ± ±1.51,c 7.92±0.98 b,c t vlue P-vlue P<0.05 compred with the preopertive level; b P<0.01 compred with the preopertive level; c P<0.05 compred with the control group. Tble V. Comprison of ADL nd NIHSS scores between the two groups before nd fter tretment (men ± SD). 1 month fter 2 months fter Items Groups n Before tretment tretment tretment ALD Control group ± ± ±8.22 b Experimentl group ± ±8.93,c 91.36±9.69 b,c t vlue P-vlue NIHSS Control group ± ± ±1.96 Experimentl group ± ±1.78,c 7.78±1.53 b,c t vlue P-vlue P<0.05 compred with the preopertive level; b P<0.01 compred with the preopertive level; c P<0.05 compred with the control group. group thn those in the control group t 1 nd 2 months fter tretment (P<0.05)(Tble III). Comprison of HAMD scores between the two groups of ptients before nd fter tretment. There were no significnt

4 4496 LI et l: GASTRODIN IN POST-STROKE DEPRESSION Tble VI. Comprison of SIS scores between the two groups before nd fter tretment (men ± SD). 1 month fter 2 months fter Items Groups n Before tretment tretment tretment Strength Control group ± ± ±7.72 Experimentl group ± ±7.72,c 82.76±9.82 b,c t vlue P-vlue Hnd function Control group ± ± ±6.31 Experimentl group ± ±6.34,c 61.94±4.66 b,c t vlue P-vlue Mood Control group ± ± ±4.15 Experimentl group ± ±4.29,c 73.74±4.86 b,c t vlue P-vlue Communiction Control group ± ± ±9.57 Experimentl group ± ±8.59,c 92.68±10.06 b,c t vlue Activity P-vlue Control group ± ± ±11.09 Experimentl group ± ±11.27,c 76.63±11.85,c t vlue Action P-vlue Control group ± ± ±11.08 Experimentl group ± ±10.45,c 83.56±12.36,c t vlue P-vlue P<0.05 compred with the preopertive level; b P<0.01 compred with the preopertive level; c P<0.05 compred with the control group. Tble VII. Comprison of tretment efficcy between the two groups. Groups n Side effects Percentge Cure Effective Ineffective Totl effective rte Control group % % Experimentl group % % χ 2 vlue P-vlue P<0.05 compred with the control group. differences in HAMD scores between the two groups before tretment (P>0.05). Compred with the preopertive levels, HAMD scores were significntly decresed in the two groups of ptients t 1 nd 2 months fter tretment (P<0.05). Compred with the control group, HAMD scores were significntly reduced in the experimentl group (P<0.05) (Tble IV). Comprison of ADL nd NIHSS scores between the two groups before nd fter tretment. As shown in Tble V, compred with the preopertive levels, ADL scores were significntly incresed nd NIHSS scores were significntly decresed in both groups t 1 nd 2 months fter tretment (P<0.05). Compred with the control group, significntly higher ADL scores nd lower NIHSS scores were found in the experimentl group t 1 nd 2 months fter tretment (P<0.05). Comprison of SIS scores between the two groups before nd fter tretment. This study evluted 6 items including strength, hnd function, mood, communiction, ctivity nd ction. As shown in Tble VI, no significnt differences in SIS scores were found between the two groups before tretment. SIS scores were significntly incresed in both groups

5 EXPERIMENTAL AND THERAPEUTIC MEDICINE 16: , t 1 month nd 2 months fter tretment (P<0.05). In ddition, SIS scores were higher in the experimentl group thn those in the control group (P<0.05). Comprison of tretment efficcy between the two groups. Two months fter tretment, 11 ptients in the control group showed side effects, 14 cses were cured, 12 cses were effective, nd 13 cses were invlid, nd the totl effective rte ws 66.67% (26/39). While, only 7 cses in the experimentl group showed side effects, 19 cses were cured, 15 cses were effective, nd 5 cses were invlid, nd the totl effective rte ws 87.18% (34/39). Therefore, tretment efficcy ws significntly higher in the experimentl group thn tht in the control group (P<0.05) (Tble VII). Discussion With n ging popultion tht continues to grow, the incidence of hypertension, dibetes, hyperlipidemi nd other stroke relted diseses re incresing, which in turn leds to the incresed incidence of stroke (8,9). PSD is the most common compliction of stroke. The incidence of PSD in Chin is estimted to be pproximtely 30-35%, nd mny ptients develop depression severl hours to severl dys fter stroke (10). There re two opposing views on the mechnism for the occurrence of PSD. It is believed tht the dmged neurl circuits of emotion regultion nd centrl nervous system induced by ischemic injury fter stroke re the min cuse of PSD (11,12). While other studies hve shown tht stroke-relted socil nd psychologicl stress is the min cuse of PSD (13,14). Conventionl tretment of PSD includes controlling hypertension, reducing high cholesterol, prohibiting smoking, blocking excittory neurotrnsmitters, preventing cerebrl ischemi, or scvenging free rdicls (15,16), but those tretments usully fil to provide stisfctory tretment outcomes. As n djunctive therpy, Chinese medicine becomes more nd more importnt in the tretment of PSD. For exmple, Hypericumperfortum extrcts hve been proven to be effective in the tretment of depression (17). In this study, gstrodin ws used to tret PSD nd showed excellent clinicl therpeutic effects. Studies hve shown tht gstrodin is n importnt component extrcted from trditionl Chinese medicine gstrodi, which is commonly used drug for clinicl tretment. Gstrodin cn remove free rdicls in the body, dely the process of poptosis, protect cell membrnes, nd simultneously expnd blood vessels nd regulte blood viscosity nd complince. In ddition, gstrodin cn inhibit the production of monomine oxidse, increse brin dopmine nd 5-HT contents, thereby exerting nxiolytic nd depressive effects (18,19). This study selected gstrodin s reserch object for the tretment of PSD nd excellent clinicl effects were observed. BDNF nd 5-HT ply pivotl roles in the regultion of synptic plsticity in dult (20). As member of the fmily of neurotrophic fctors, BDNF plys pivotl role in brin development nd plsticity by promoting nerve regenertion, synptic plsticity nd cell survivl (21,18). 5-HT is produced by neurons locted in the brin stem, nd it cn lso promote the survivl of neurons in the dult brin (19). The xons tht produce 5-HT neurons dominte normtive behvior in multiple cerebrl corticl nd subcorticl regions including cognition nd mood (22,23). Disrupted 5-HT nd BDNF signling pthwys re the min cuses of depression, nd studying the levels of 5-HT nd BDNF in PSD ptients is n importnt wy to expose the moleculr mechnism. In this study, we found tht gstrodin could significntly increse the levels of 5-HT nd BDNF in ptients with PSD. In ddition, HAMD nd NIHSS scores were significntly decresed nd ADL nd SIS scores were significntly incresed t 1 nd 2 months fter tretment with gstrodin. Compred with fluoxetine hydrochloride, gstrodin hs less side effects nd good efficiency. Gstrodin cn effectively llevite depression nd improve the qulity of life of ptients. In conclusion, gstrodin cn be used to effectively tret PSD nd should be populrized in clinicl prctices. Acknowledgements Not pplicble. Funding No funding ws received. Avilbility of dt nd mterils The dtsets used nd/or nlyzed during the present study re vilble from the corresponding uthor on resonble request. Authors' contributions GL drfted the mnuscript. GL nd YM were minly devoted to collecting nd interpreting the dt. JJ nd XS revised it criticlly for importnt intellectul content nd were lso involved in the conception nd design of the study. QF ws responsible for the conception nd design of the study. All uthors hve red nd pproved the finl mnuscript. Ethics pprovl nd consent to prticipte The study ws pproved by the Ethics Committee of Binzhou City Center Hospitl (Binzhou, Chin). Signed informed consents were obtined from the ptients. Ptient consent for publiction Not pplicble. 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