Thespinocerebellar ataxias (SCAs) are clinically and genetically a heterogeneousgroup of neurodegenerative disorders. At present, we have no effectivetherapeutic tools.
Previous studies haveshown for the first time, the successful treatment of spinocerebellar ataxia bymedicinal herbs 4,5. Here we reportthe herbal therapy for an another case of spinocerebelalar ataxia 6 withtypical symptoms. A 71-year-old female suffered from ataxia of gait and stance,limb ataxia and dysarthria. Genetic tests revealed an expanded allele of22 CAG repeats at the spinocerebellar ataxia type 6 locus. She was diagnosed asspinocerebellar ataxia 6.
A mixture of 21 medicinal herbs (a modification of ZhenganXifeng Tang) was given according to the differential diagnosis basedon the guideline of traditional Chinese medicine. Most of the symptoms were remarkably improvedafter 60 days of the herbal treatment. Ataxia of gait and stance disappeared and her total ataxia score wasimproved from 26 to 12 on a 100-point semiquantitative InternationalCooperative Ataxia Rating Scales(ICARS). Together with the previous report, the results implytherapeutic potential of the medicinal herbs for spinocerebellar ataxia 6. Keywords: ataxia,CAG repeat, genetic disease, herbal therapy, polyglutamine. Introduction The spinocerebellarataxias (SCAs) are clinically and genetically a heterogeneous group ofneurodegenerative disorders. Althoughtransient improvement of the ataxia with thyrotropin-releasing hormone,branched-chain amino acid, or zolpidem have been reported 1-3, we have noeffective therapeutic tools against the degenerative diseases. Previous studies for the firsrt time, havedemonstrated the successful treatment of twocasesof spinocerebellar ataxia 6 by systems therapy with medicinal herbs 4,5.
The remedy used forthese cases consists of different types of herbs such as sedative, anticonvulsive,neuroprotective, neuroregulatory and DNA binding herbs. Mostof the symptoms were remarkably improved after 60 days of the initial herbaltreatment. Even after the first or the second relapse, the neurologicalsymptoms were markedly improved with the herbal therapy within 60 days 4. In order to see whether the herbal therapycould be effective against the other cases of SCA6, medicinal herbs (amodification of Zhengan Xifeng Tang)4,5 were given for an another patientwith SCA6. We report here an anothersuccessful treatment of SCA6 with the medicinal herbs.A71-year-old female suffered from titubation, loss of balance and dysarthria wasdiagnosed as spinocerebellar ataxia. Dysarthria and loss of balance had graduallyprogressed until she could not walk well for these three years. Tendon reflexeswere not increased.
Considerably slow and dysarthric speech and definiteslurring were observed. Mild ataxia wasfound on the lower extremities but not on the upper extremities. There wereslight abnormalities of ocular saccadic pursuit. Autonomic disorders were not found. To identify various subtypesof spinocerebellar ataxias(SCAs), SCA1, SCA2, DRPLA(Dentatorubral-pallidoluysian atrophy), SCA3/MJD (Machado-Joseph disease),SCA6, SCA7 ,SCA8, SCA10 and SCA17 lociwere assessed for expansion of trinucleotide repeats. Analysis of the SCA6 CAG trinucleotiderepeat at the CACNA1A gene in the patient’s DNA demonstrated an expanded alleleof 22 CAG repeat units 6,7. The results of all other testing of DNArepeat expansion mutations associated with 9 different ataxias were withinnormal ranges. She was diagnosed asSCA6.
For the systems therapy withmedicinal herbs, the differential diagnosis by traditional herbal medicine wasmade according to the guideline 8. Amixture of 21 medicinal herbs (Uchida Wakanyaku Co. Ltd, Tokyo, Japan) (amodification of Zhengan Xifeng Tang) was boiled and the supernatant wasadministered three times a day for 60 days (Table 1), which was expected tostabilize central nervous system and usually used against tremor, vertigo, or ataxia in traditionalChinese medicine 5. Most of thesymptoms including gait ataxia and titubation were remarkably improved after 60days of the treatment.
Dysarthric speechand slurring was apparently improved but not completely recovered to normal.Total ataxia score was improved from 26 to 12 on a one-hundred-pointsemi-quantitative International Cooperative Ataxia Rating Scale (ICARS) 9. Score for postural and gait disturbances(Test No. 1-7) was reduced from initial score of 9/34 to 0/34 (Fig. 1). Limb ataxia score (Test No. 8-14) wasdecreased from 12/52 to 7/52. However,disarthria score (Test No.
15,16) was not apparently improved after the herbaltreatment (5/8). To consolidate the effect of the medicinal herbs, the sameremedy was given for another 60 days. Noadverse effects were observed.Discussion A case of SCA6 was successfully treatedwith a mixture of 22 medicinal herbs (a modification of Zhengan XifengTang). Most of the symptoms dramaticallyimproved after 60 days of the treatment. Most of the ingredients included in the recipe were common to those usedfor the first case of SCA6 in our previous report 4,5. Theremedy used for this case consists of several different ingredients, which havewell-established histories of use for treatment of vertigo, tremor, andataxia in Asiancountries and are expected to exert their specificeffects 5. The ingredients include sedative,anticonvulsive, neuroprotective, neurorefgulatory and DNA binding herbs.
The formula ischemically quite complex with hundreds of constituents. While the exactchemical nature and interaction of all these constituents are not well known, the followingbioactivities have been demonstrated in the ingredients of this formula. An anticonvulsive herb, Gastrodia elata,a component of our modified ZhenganXifeng Tang has been shown to protect against kainicacid-induced neuronal damages in the mouse hippocampus10. Uncariarhynchophylla Jacks when combined with Gastrodiaelata exhibited greater anticonvulsiveeffect in kainic acid treated rats 11. The methanol exract of FossiliaMatoidi OSSIS showed anxiolysis, andanticonvulsive activity in mice 12. The ethanol extracts of Paeonialactiflora root, an another component of the modified ZhenganXifeng Tang and its active constituents,gallic acid and methyl gallate, exhibited a significant free radical scavengingeffect against 1,1-diphenyl-2-picryl hydrazine radical generation and had aninhibitory effect on lipid peroxidation. In addition, they strongly inhibitedthe hydrogen peroxide-induced DNA damage in mammalian cells 13.
Recently, paeoniflorin, a major activeconstituent of Paeonia lactiflora has been shown to attenuateneuroinflammation and doperminergic neurodegeneration by activation ofadenosine A1 receptor 14. Berberine, a majoralkaloid component contained in Coptis chinensis Franch had neuroprotective actions against in vitro ischemia-induced neuronalcell damage in organotypic hippocampal slice cultures 15. Alkaloid fraction of Uncaria rhynchophylla wasshown to have a protective property against N-methyl-D-aspartate(NMDA)-inducedcytotoxicity by suppressing the NMDA-induced apoptosis in rat hippocampalslices 16. In addition, Polygalaeradix extracts have been shown to inhibit NMDA-induced neuronal cell death in rat cerebellar granule neurons 17.Together with these observations, it is possible to consider that some herbs inthis modified ZhenganXifeng Tang exert theirtherapeutic effects through their anticonvulsive and neuroprotective activitiesagainst neuronal degeneration in cerebellum.
Recently, SCA6 has been demonstrated to be an autosomal dominant cerebellar ataxia associated withsmall polyglutamine-dependent expansions in the alpha 1A-voltage calciumchannel 6. Berberine, palmatine andjatrorrrhizine, major constituents of Coptis chinensis Franch have been shownto bind calf thymus DNA 18. Berberine binds to humantelomeric DNA as G-quadruplex stabilizing ligand 19. Further extensive investigations are requiredto cralify the mechanisms by which the remission induction of this genetic disease of CAGrepeat expansion mutation, has been attained with themedicinal herbs.
Anyway, together withour previous reports 4,5, the findings of the present case imply thetherapeutic potential of herbal medicine for this hereditary neurodegenerativedisorder.