Amin, Navin M

Broeske, Daniel J

Feinstein, Douglas L

Heneka, Michael T

Pershadsingh, Harrihar A

Saini, Rashmi

eScholarship - University of California

UC IrvineUC Irvine Previously Published WorksTitleEffect of pioglitazone treatment in a patient with secondary multiple sclerosisPermalinkhttps://escholarship.org/uc/item/4r66z6j7JournalJournal of Neuroinflammation, 1(1)ISSN17422094AuthorsPershadsingh, Harrihar AHeneka, Michael TSaini, Rashmiet al.Publication Date2004DOI10.1186/1742-2094-1-3 Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaBioMed CentralJournal of NeuroinflammationssOpen AcceCase reportEffect of pioglitazone treatment in a patient with secondary multiple sclerosisHarrihar A Pershadsingh*1,2, Michael T Heneka2, Rashmi Saini1, Navin M Amin1, Daniel J Broeske3 and Douglas L Feinstein4Address: 1Departments of Family Medicine, Kern Medical Center, Bakersfield, and University of California, Irvine, California, USA, 2Department of Neurology, University of Bonn, Bonn, Germany, 3Department of Internal Medicine, Kern Medical Center, Bakersfield, California, USA and 4Department of Anesthesiology, University of Illinois, Chicago, Illinois, USAEmail: Harrihar A Pershadsingh* - pershadh@kernmedctr.com; Michael T Heneka - Michael.Heneka@ukb.uni-bonn.de; Rashmi Saini - pershadh@kernmedctr.com; Navin M Amin - aminn@kernmedctr.com; Daniel J Broeske - broeske1@juno.com; Douglas L Feinstein - dlfeins@Uic.edu* Corresponding author    Multiple sclerosisthiazolidinedionePPARγpioglitazoneinflammationAbstractBackground: Ligands of the peroxisome proliferator-activated receptor-gamma (PPARγ) induceapoptosis in activated T-lymphocytes and exert anti-inflammatory effects in glial cells. Preclinicalstudies have shown that the thiazolidinedione pioglitazone, an FDA-approved PPARγ agonist usedto treat type 2 diabetes, delays the onset and reduces the severity of clinical symptoms inexperimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS). Wetherefore tested the safety and therapeutic potential of oral pioglitazone in a patient withsecondary MS.Case presentation: The rationale and risks of taking pioglitazone were carefully explained to thepatient, consent was obtained, and treatment was initiated at 15 mg per day p.o. and then increasedby 15 mg biweekly to 45 mg per day p.o. for the duration of the treatment. Safety was assessed bymeasurements of metabolic profiles, blood pressure, and edema; effects on clinical symptoms wereassessed by measurement of cognition, motor function and strength, and MRI. Within 4 weeks thepatient exhibited increased appetite, cognition and attention span. After 12 months treatment,body weight increased from 27.3 to 35.9 kg (32%) and maintained throughout the duration of thestudy. Upper extremity strength and coordination improved, and increased fine coordination wasnoted unilaterally after 8 months and bilaterally after 15 months. After 8 months therapy, thepatient demonstrated improvement in orientation, short-term memory, and attention span. MRIscarried out after 10 and 18 months of treatment showed no perceptible change in overall brainatrophy, extent of demyelination, or in Gd-enhancement. After 3.0 years on pioglitazone, thepatient continues to be clinically stable, with no adverse events.Conclusions: In a patient with secondary progressive MS, daily treatment with 45 mg p.o.pioglitazone for 3 years induced apparent clinical improvement without adverse events.Pioglitazone should therefore be considered for further testing of therapeutic potential in MSpatients.Published: 20 April 2004Journal of Neuroinflammation 2004, 1:3Received: 24 March 2004Accepted: 20 April 2004This article is available from: http://www.jneuroinflammation.com/content/1/1/3© 2004 Pershadsingh et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.Page 1 of 4(page number not for citation purposes)Journal of Neuroinflammation 2004, 1 http://www.jneuroinflammation.com/content/1/1/3BackgroundCurrent therapies for MS are limited in efficacy and canhave adverse effects. Although immuno-modulating type-1β interferons and glatiramer acetate reduce active CNSinflammatory lesions, clinical severity and attack fre-quency in relapsing remitting MS, they are less efficaciousin progressive disease [1]. The immunosuppressive agent,mitoxantrone is presently approved for treating progres-sive MS but is limited because of severe adverse side-effects especially cardiotoxicity [1]. The insulin-sensitizinganti-diabetic thiazolidinediones (TZDs) are high affinityactivators of the nuclear transcription factor peroxisomeproliferator-activated receptor-gamma (PPARγ). TZDsinhibit T lymphocyte proliferation and activation, reduceexpression and production of inflammatory moleculesincluding interleukin-1β, tumor necrosis factor-α andinducible nitric oxide synthase, increase astrocyte metab-olism and resistance to cytotoxicity [11], and reduce clin-ical symptoms in experimental autoimmuneencephalomyelitis (EAE), an autoimmune-mediated,demyelinating disease which provides a model for MS[2,3]. In view of these effects and the established safetyprofile of TZDs, we investigated the therapeutic potentialof the FDA-approved anti-diabetic TZD pioglitazone in apatient with secondary progressive MS.Case presentationA 44-year-old woman with secondary progressive MS wasdiagnosed at age 20 yr, per Lublin and Reingold [4]. Dur-ing the next 15 years she had 8 documented relapseswhich resolved with intravenous glucocorticoid therapy.The relapses decreased in frequency during this time, afterwhich her clinical status deteriorated, with progressivedevelopment of quadriparesis, ataxia, fatigue and cogni-tive decline. In 1994, a trial of interferon β-1b was discon-tinued because of increased spasticity, and she was not acandidate for glatiramer. She had no history of diabetes,cardiovascular, liver or kidney disease.When seen in 1999 her weight was 29.5 kg, down from54.5 kg in 1976. She was paraplegic, wheelchair-bound,and exhibited paresis of the upper extremities with OMS(Oxford Muscle Strength) score of 2–3 out of 5 (Table 1)and an EDSS score of 8.0. Neurological presentationincluded paraplegia, bilateral central scotomata with vis-ual-field loss, dysphagia, chronic fatigue, cognitiveimpairment similar to mild dementia, and depressedmood. In June 2000, having explained the rationale andrisks, she consented to a trial of pioglitazone, which wasinitiated at 15 mg daily and increased by 15 mg biweeklyto 45 mg. Improvement was evident within 4 weeks asincreased appetite, cognition and attention span. Herweight increased from 27.3 to 35.9 kg (32%) after 12months treatment, which was maintained between 34.6to 36.2 kg throughout an additional 18 months. Weightgain was evident as increased muscle mass and peripheralfat, mainly in the hips, gluteal area, and limbs. Upperextremity strength and coordination progressivelyimproved (Table 1). Improved fine coordination wasnoted unilaterally after 8 months (left finger-to-nose exe-cution), and bilaterally after 15 months. Before pioglita-zone, repetitive statements and forgetfulness, reminiscentof dementia, were problematic. After 8 months therapy,cognitive assessment demonstrated improvement in ori-entation, short-term memory (recall increased from 0/3 to2/3 objects), attention span, registration and insight, andis consistent with clinical improvement [5]. According toDSM IV criteria, her depression also improved signifi-cantly, along with the progressive gain in weight andimprovement in neurological function as a whole. Shewas progressively able to tolerate outdoor social activitiesfor several hours at a time, with improved stamina andwell-being.Table 1: Upper Extremity Muscle Strength Before and After 52 Weeks on PioglitazoneMuscle Strength GradeMuscle Group/Function Before PIO (Baseline) 15 months After PIO 30 months After PIORight Left Right Left Right LeftHand Flexor Group/Grip 2 3 4 5 4 5Bicep/Arm Flexion 2 3 4 5 4 5Tricep/Arm Extension 1 2 4 5 4 5Shoulder Flexion 1 2 4 5 4 5Shoulder Abduction 2 3 4 5 4 5Muscle strength determined using the Oxford Muscle Strength Grading Scale (Grade 0 = No movement; Grade 3 = Completely moves body part against gravity; Grade 5 = Normal)Page 2 of 4(page number not for citation purposes)Journal of Neuroinflammation 2004, 1 http://www.jneuroinflammation.com/content/1/1/3During the study, two MRI studies with gadolinium (Gd)were performed, one 18 months after initiation of piogli-tazone and the second 10 months later (Figure 1). Therewas no perceptible change in overall brain atrophy, extentof demyelination, or in Gd-enhancement indicating thatat least over the 10 months between the MRI studies, thedisease was quiescent. This also suggests that the benefi-cial effects of pioglitazone treatment were not associatedwith any overt improvement in pathology. After 3 yearson pioglitazone, she continues to be clinically stable.There have been no adverse events, and her metabolicprofile has remained normal throughout the study.ConclusionsThe limited efficacy and safety of immuno-modulatoryand immuno-suppressive agents available for treatingprogressive MS warrants development of improved andsafer therapies [1]. MS is an autoimmune disease associ-ated with inappropriate T lymphocyte activation, CNSinflammation and demyelination, resulting in axonal andneuronal damage [1]. The thiazolidinedione class of drugswere developed for the treatment of type 2 diabetes andact by improving insulin resistance without causinghypoglycemia, even in euglycemic individuals. They werelater found to activate PPARγ and shown to promote anti-inflammatory and immunosuppressive effects by sup-pressing T lymphocyte activation, proliferation, andinhibiting cellular production of inflammatory moleculesassociated with MS [3,6,7].The beneficial effects of pioglitazone observed in thispatient are somewhat unexpected as inflammation is lessAxial T1-weighted fluid-attenuated inversion recovery (FLAIR) MRI images showing confluent demyelinationFigure 1Axial T1-weighted fluid-attenuated inversion recovery (FLAIR) MRI images showing confluent demyelination. MRIs were taken at 10 months (left) and at 18 months (right) after initiation of treatment with pioglitazone. Similar axial sections are shown for the two time points.10 months 18 monthsPage 3 of 4(page number not for citation purposes)Journal of Neuroinflammation 2004, 1 http://www.jneuroinflammation.com/content/1/1/3Publish with BioMed Central   and  every scientist can read your work free of charge"BioMed Central will be the most significant development for disseminating the results of biomedical research in our lifetime."Sir Paul Nurse, Cancer Research UKYour research papers will be:available free of charge to the entire biomedical communitypeer reviewed and published immediately upon acceptancecited in PubMed and archived on PubMed Central yours — you keep the copyrightSubmit your manuscript here:http://www.biomedcentral.com/info/publishing_adv.aspBioMedcentralprominent in secondary progressive MS compared torelapsing remitting disease. However, improvements inupper body strength, coordination, dysphagia, and cogni-tive function, suggest neurological benefit associated withpioglitazone treatment. In addition to their anti-inflam-matory actions, TZDs can also influence cell physiology ina receptor-independent manner, and we recently demon-strated that TZDs increase astrocyte glucose metabolismand lactate production [11]. It is therefore feasible thateffects on brain metabolism, for example increased capac-ity of astrocytes to provide lactate to surrounding neurons,accounts in part for improved cognitive and motor func-tion. However, the persistence of lower extremity paralysisappears a likely consequence of irreversible spinal cordatrophy. The 30% gain in weight markedly exceeds theapproximately 2–4% weight gain seen with diabetics [seeprescribing information: ACTOS® (pioglitazone hydro-chloride), Takeda Chemical Co.]. While this may reflectdecreased depression, there are as yet no reports thatpioglitazone or any other thiazolidinedione, influencemood disorders.In EAE mice pioglitazone decreased disease incidence,reduced maximum disease severity, and induced remis-sion in already-ill animals [3]. Similar results wereobtained with other TZDs including rosiglitazone,another approved antidiabetic drug [3]. These drugs havealso been shown to clinically ameliorate other inflamma-tory diseases [8] including psoriasis [9] and ulcerative col-itis [10]. Described adverse effects for pioglitazone areconfined to the diabetic population, and include mildedema, and limited weight gain, and pioglitazone has notbeen causally linked to hepatic failure, as has troglitazone.These findings imply that pioglitazone, and perhaps otherinsulin-sensitizing TZDs may provide therapeutic benefitin MS.AbbreviationsDSM, diagnostic and statistical manual of mental disor-ders; FLAIR, fluid attenuation inversion recovery; Gd,gadolinium; MRI, magnetic resonance imaging; MS, mul-tiple sclerosis; PIO, pioglitazone; PPARγ, peroxisomeproliferator-activated receptor gamma; TZD,thiazolidinedione.Competing interestsNone declared.Authors' contributionsHAP was the primary physician, conceived of the originalstudy, and prepared first draft of the manuscript. MTHwas a consulting neurologist, evaluated MRI data, assistedwith manuscript editing, and contributed to the originalidea of treating MS patients with TZDs. RS performed clin-ical assessments. NM and DJB consulted on clinical eval-uations and response to therapy. DLF organized andanalyzed data, contributed to the original idea to treat MSpatients with TZDs, helped write and edit, and wrote thefinal draft of the manuscript.AcknowledgementsWe thank Monica Menendez for secretarial assistance. Supported by grants from the National Multiple Sclerosis Society (DLF), Takeda Pharmaceuticals (DLF) and Bethesda Pharmaceuticals, Inc (HAP). Written consent was obtained from the patient for publication of study.References1. Keegan BM, Noseworthy JH: Multiple sclerosis. Annu Rev Med2002, 53:285-302.2. Niino M, Iwabuchi K, Kikuchi S, et al.: Amelioration of experimen-tal autoimmune encephalomyelitis in C57BL/6 mice by anagonist of peroxisome proliferator-activated receptor-gamma. J Neuroimmunol 2001, 116:40-48.3. Feinstein DL, Galea E, Gavrilyuk V, et al.: Prevention and treat-ment of experimental autoimmune encephalomyelitis bypioglitazone, a PPAR-γ agonist. Ann Neurol 2002, 51:694-702.4. Lublin FD, Reingold SC: Defining the clinical course of multiplesclerosis: results of an international survey. National Multi-ple Sclerosis Society (USA) Advisory Committee on ClinicalTrials of New Agents in Multiple Sclerosis. Neurology 1996,46:907-911.5. DeSousa EA, Albert RH, Kalman B: Cognitive impairments inmultiple sclerosis: a review. Am J Alzheimers Dis Other Demen2002, 17:23-9.6. Debril MB, Renaud JP, Fajas L, Auwerx J: The pleiotropic functionsof peroxisome proliferator-activated receptor-γ. J Mol Med2001, 79:30-47.7. Clark RB: The role of PPARs in inflammation and immunity. JLeukoc Biol 2002, 71:388-400.8. Pershadsingh HA: PPAR-gamma-Therapeutic target for dis-eases beyond diabetes: 2uo vadis? Expert Opin Investig Drugs 2004,13:212-215.9. Ellis CN, Varani J, Fisher GJ, et al.: Troglitazone improves psoria-sis and normalizes models of proliferative skin disease: lig-ands for peroxisome proliferator-activated receptor-gammainhibit keratinocyte proliferation. Arch Dermatol 2000,136:609-16.10. Lewis JD, Lichtenstein GR, Stein RB, et al.: An open-label trial ofthe PPAR-gamma ligand rosiglitazone for active ulcerativecolitis. Am J Gastroenterol 2001, 96:3323-8.11. Dello Russo C, Galea E, Gavrilyuk V, Weinberg G, Palmer J, AlmeidaA, Bolanos JP, Pelligrino D, Feinstein DL: PPARγ agonists increaseglucose metabolism in astrocytes. J Biol Chem 2003,278:5828-36.Page 4 of 4(page number not for citation purposes)

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