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Journal of Neurorestoratology  2021, Vol. 9 Issue (2): 117-136    doi: 10.26599/JNR.2021.9040010
Research Article     
Improved survival in amyotrophic lateral sclerosis patients following autologous bone marrow mononuclear cell therapy: a long term 10-year retrospective study
Alok Sharma1,Hemangi Sane2,Amruta Paranjape2,3,(✉)(),Ritu Varghese2,Vivek Nair3,Hema Biju3,Dhanashree Sawant2,Nandini Gokulchandran1,Prerna Badhe4
1Department of Medical Services and Clinical Research, NeuroGen Brain and Spine Institute, Navi Mumbai 400706, Maharashtra, India
2Department of Research and Development, NeuroGen Brain and Spine Institute, Navi Mumbai 400706, Maharashtra, India
3Department of Neurorehabilitation, NeuroGen Brain and Spine Institute, Navi Mumbai 400706, Maharashtra, India
4Department of Regenerative Laboratory Services, NeuroGen Brain and Spine Institute, Navi Mumbai 400706, Maharashtra, India
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Abstract  Background:

Promising results from previous studies using cell therapy have paved the way for an innovative treatment option for amyotrophic lateral sclerosis (ALS). There is considerable evidence of immune and inflammatory abnormalities in ALS. Bone marrow mononuclear cells (BMMNCs) possess immunomodulatory properties and could contribute to slowing of disease progression.


Aim of our study was to evaluate the long-term effect of autologous BMMNCs combined with standard treatment on survival duration in a large population and to evaluate effect of type of onset and hormonal status on survival duration in the intervention group.


This controlled, retrospective study spanned over 10 years, 5 months; included 216 patients with probable or definite ALS, 150 in intervention group receiving autologous BMMNCs and standard treatment, and 66 in control group receiving only standard treatment. The estimated survival duration of control group and intervention group was computed and compared using Kaplan Meier analysis. Survival duration of patients with different types of onset and hormonal status was compared within the intervention group.


None of the patients reported any major adverse events related to cell administration or the procedure. Kaplan Meier analysis estimated survival duration in the intervention group to be 91.7 months while 49.7 months in the control group (p = 0.008). Within the intervention group, estimated survival was significantly higher (p = 0.013) in patients with limb onset (102.3 months) vs. bulbar onset (49.9 months); premenopausal women (93.1 months) vs. postmenopausal women (57.6 months) (p = 0.002); and preandropausal men (153.7 months) vs. postandropausal males (56.5 months) (p = 0.006).


Cell therapy using autologous BMMNCs along with standard treatment offers a promising and safe option for ALS with the potential of long term beneficial effect and increased survival. Limb onset patients, premenopausal women and men ≤ 40 years of age demonstrated better treatment efficacy.

Key wordsautologous bone marrow mononuclear cells      cellular therapy      amyotrophic lateral sclerosis      motor neuron disease      pre-menopausal women      pre-andropausal men      cell therapy     
Received: 24 May 2021      Published: 19 October 2021
Corresponding Authors: Amruta Paranjape     E-mail:
Cite this article:

Alok Sharma,Hemangi Sane,Amruta Paranjape,Ritu Varghese,Vivek Nair,Hema Biju,Dhanashree Sawant,Nandini Gokulchandran,Prerna Badhe. Improved survival in amyotrophic lateral sclerosis patients following autologous bone marrow mononuclear cell therapy: a long term 10-year retrospective study. Journal of Neurorestoratology, 2021, 9: 117-136.

URL:     OR

Fig. 1Study protocol and outcome measures.
DemographicsIntervention groupControl group
No. of females (percentage)51 (34%)19 (28.79%)
No. of males (percentage)99 (66%)47 (71.21%)
Intramuscular Injection
Patients received intramuscular transplantation of cells (percentage)47 (31.3%)0 (0)
Patients not received intramuscular transplantation of cells (percentage)103 (68.7%)66 (100%)
Patients prescribed lithium (percentage)125 (83.3%)0 (0)
Patients not prescribed lithium (percentage)25 (16.7%)66 (100%)
Edaravone taken (percentage)19 (12.7%)4 (6.01%)
Edaravone not taken (percentage)131 (87.3%)62 (93.94%)
Testosterone injection prescribed (percentage)23 (23.2%)0 (0)
Testosterone injection not prescribed (percentage)76 (76.8%)66 (100%)
Type of Onset
Patients with bulbar onset (percentage)34 (22.7%)16 (24.2%)
Patients with limb onset (percentage)116 (77.3%)50 (75.8%)
The average age at onset in years (SD)50 (10)54 (9)
Table 1Demographic data of the study population.
Adverse eventsPercentage adverse events immediately post-interventioncell-related adverse events
Spinal headache13.3 %None
Nausea and/or vomiting7.0 %
Pain at the aspiration site3.8 %
Backache/pain at the injection site10.1 %
Fatigue2.7 %
Constipation8.2 %
Loose motion1.9 %
Sudden onset of respiratory discomfortNoneNone
Neurological deficitsNone
Paresthesia/loss of sensation in lower limbNone
Cardiac failureNone
Hematoma at the injection siteNone
Table 2Adverse events observed in the post-intervention period.
Premenopausal womenPostmenopausal womenPreandropausal menPostandropausal men
Distribution of mortality6 (5.9%)31 (30.4%)14 (13.7%)51 (50%)
Table 3Percentage distribution of deaths within intervention group in premenopausal and postmenopausal women, preandropausal and postandropausal men.
Intervention groupControl groupp value
Estimated survival duration (months)91.749.70.008*
Table 4Kaplan-Meier analysis of survival duration for patients with and without cell therapy.
Fig. 2Kaplan-Meier graph showing comparison of the estimated survival duration in intervention and control groups. Mean estimated survival duration was 91.7 months in the intervention group while in the control group it was 49.7 months (p = 0.008*). *Indicates a statistically significant difference between the groups.
Prognostic factorsEstimated survival duration (months) as calculated by Kaplan-Meier survival analysisStatistical significance
Onset type
Bulbar onset49.90.013*
Limb onset102.3
Hormonal status (Women)
Premenopausal women93.10.002*
Postmenopausal Women57.6
Hormonal status (Males)
Preandropausal men153.70.006*
Postandropausal men56.5
Table 5Effect of prognostic factors on survival duration within the intervention group.
Fig. 3Comparison of survival duration among the subgroups within the intervention group. (A) Bulbar onset vs. limb onset groups; (B) premenopausal vs. postmenopausal women; and (C) preandropausal vs. postandropausal men.
[1]   Cleveland DW, Rothstein JD. From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nat Rev Neurosci 2001, 2(11): 806-819.
[2]   Wijesekera LC, Nigel Leigh P. Amyotrophic lateral sclerosis. Orphanet J Rare Dis 2009, 4(1): 1-22.
[3]   Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev 2012(3): CD001447.
[4]   Tanaka M, Sakata T, Palumbo J, et al. A 24-week, phase III, double-blind, parallel-group study of edaravone (MCI-186) for treatment of amyotrophic lateral sclerosis (ALS). Neurology 2016, 86(16 ): P3. 189.
[5]   Oskarsson B, Gendron TF, Staff NP. Amyotrophic lateral sclerosis: an update for 2018. Mayo Clin Proc 2018, 93(11): 1617-1628.
[6]   Tanaka M, Akimoto M, Palumbo J, Sakata T. A double-blind, parallel-group, placebo-controlled, 24-week, exploratory study of edaravone (MCI-186) for the treatment of advanced amyotrophic lateral sclerosis (ALS). Neurology 2016, 86(16 ): P3. 191.
[7]   Abe K, Itoyama Y, Sobue G, et al. Confirmatory double-blind, parallel-group, placebo-controlled study of efficacy and safety of edaravone (MCI-186) in amyotrophic lateral sclerosis patients. Amyotroph Lateral Scler Frontotemporal Degener 2014, 15(7/8): 610-617.
[8]   Al-Chalabi A, Brown RH Jr. Finding a treatment for ALS - will gene editing cut it? N Engl J Med 2018, 378(15): 1454-1456.
[9]   Moura MC, Novaes MRCG, Zago YSSP, et al. Efficacy of stem cell therapy in amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Clin Med Res 2016, 8(4): 317-324.
[10]   Beers DR, Zhao WH, Liao B, et al. Neuroinflammation modulates distinct regional and temporal clinical responses in ALS mice. Brain Behav Immun 2011, 25(5): 1025-1035.
[11]   Rizzo F, Riboldi G, Salani S, et al. Cellular therapy to target neuroinflammation in amyotrophic lateral sclerosis. Cell Mol Life Sci 2014, 71(6): 999-1015.
[12]   Blanquer M, Pérez Espejo MA, Iniesta F, et al. Bone marrow stem cell transplantation in amyotrophic lateral sclerosis: technical aspects and preliminary results from a clinical trial. Methods Find Exp Clin Pharmacol 2010, 32(): 31-37.
[13]   Blanquer M, Moraleda JM, Iniesta F, et al. Neurotrophic bone marrow cellular nests prevent spinal motoneuron degeneration in amyotrophic lateral sclerosis patients: a pilot safety study. Stem Cells 2012, 30(6): 1277-1285.
[14]   Prabhakar S, Marwaha N, Lal V, et al. Autologous bone marrow-derived stem cells in amyotrophic lateral sclerosis: a pilot study. Neurol India 2012, 60(5): 465-469.
[15]   Sharma AK, Sane HM, Paranjape AA, et al. The effect of autologous bone marrow mononuclear cell transplantation on the survival duration in amyotrophic lateral sclerosis - a retrospective controlled study. Am J Stem Cells 2015, 4(1): 50-65.
[16]   General Assembly of the World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. J Am Coll Dent 2014, 81(3): 14-18.
[17]   Feldman HA, Longcope C, Derby CA, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab 2002, 87(2): 589-598.
[18]   Zmuda JM, Cauley JA, Kriska A, et al. Longitudinal relation between endogenous testosterone and cardiovascular disease risk factors in middle-aged men. A 13-year follow-up of former Multiple Risk Factor Intervention Trial participants. Am J Epidemiol 1997, 146(8): 609-617.
[19]   Longinetti E, Fang F. Epidemiology of amyotrophic lateral sclerosis: an update of recent literature. Curr Opin Neurol 2019, 32(5): 771-776.
[20]   Pupillo E, Messina P, Logroscino G, et al. Long-term survival in amyotrophic lateral sclerosis: a population-based study. Ann Neurol 2014, 75(2): 287-297.
[21]   Chio A, Logroscino G, Hardiman O, et al. Prognostic factors in ALS: A critical review. Amyotroph Lateral Scler 2009, 10(5-6): 310-323.
[22]   Testa D, Lovati R, Ferrarini M, et al. Survival of 793 patients with amyotrophic lateral sclerosis diagnosed over a 28-year period. Amyotroph Lateral Scler Other Motor Neuron Disord 2004, 5(4): 208-212.
[23]   del Aguila MA, Longstreth WT Jr, McGuire V, et al. Prognosis in amyotrophic lateral sclerosis: a population-based study. Neurology 2003, 60(5): 813-819.
[24]   Tysnes OB, Vollset SE, Aarli JA. Epidemiology of amyotrophic lateral sclerosis in Hordaland County, western Norway. Acta Neurol Scand 1991, 83(5): 280-285.
[25]   Chiò A, Logroscino G, Traynor BJ, et al. Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature. Neuroepidemiology 2013, 41(2): 118-130.
[26]   Manjaly ZR, Scott KM, Abhinav K, et al. The sex ratio in amyotrophic lateral sclerosis: A population based study. Amyotroph Lateral Scler 2010, 11(5): 439-442.
[27]   Gutiérrez-Lobos K, Scherer M, Anderer P, et al. The influence of age on the female/male ratio of treated incidence rates in depression. BMC Psychiatry 2002, 2: 3.
[28]   Sane H, Sharma A, Paranjape A, et al. Autologous bone marrow mononuclear cell intrathecal transplantation may affect the survival duration in amyotrophic lateral sclerosis-Clinical study. In Theme 14, Therapeutic Strategies, Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. Orlando, USA: Taylor & Francis Online, 2015, pp. 227-249.
[29]   Nakamizo T, Urushitani M, Inoue R, et al. Protection of cultured spinal motor neurons by estradiol. Neuroreport 2000, 11(16): 3493-3497.
[30]   Groeneveld GJ, Van Muiswinkel FL, Sturkenboom JM, et al. Ovariectomy and 17beta-estradiol modulate disease progression of a mouse model of ALS. Brain Res 2004, 1021(1): 128-131.
[31]   Monachelli GG, Meyer M, Rodríguez GE, et al. Endogenous progesterone is associated to amyotrophic lateral sclerosis prognostic factors. Acta Neurol Scand 2011, 123(1): 60-67.
[32]   Gonzalez Deniselle MC, López-Costa JJ, Saavedra JP, et al. Progesterone neuroprotection in the Wobbler mouse, a genetic model of spinal cord motor neuron disease. Neurobiol Dis 2002, 11(3): 457-468.
[33]   Gonzalez Deniselle MC, Garay L, Gonzalez S, et al. Progesterone modulates brain-derived neurotrophic factor and choline acetyltransferase in degenerating Wobbler motoneurons. Exp Neurol 2007, 203(2): 406-414.
[34]   Chió A, Meineri P, Tribolo A, et al. Risk factors in motor neuron disease: a case-control study. Neuroepidemiology 1991, 10(4): 174-184.
[35]   Popat RA, van den Eeden SK, Tanner CM, et al. Effect of reproductive factors and postmenopausal hormone use on the risk of amyotrophic lateral sclerosis. Neuroepidemiology 2006, 27(3): 117-121.
[36]   Gonzalez Deniselle MC, Liere P, Pianos A, et al. Steroid profiling in male wobbler mouse, a model of amyotrophic lateral sclerosis. Endocrinology 2016, 157(11): 4446-4460.
[37]   McLeod VM, Lau CL, Chiam MDF, et al. Androgen receptor antagonism accelerates disease onset in the SOD1G93A mouse model of amyotrophic lateral sclerosis. Br J Pharmacol 2019, 176(13): 2111-2130.
[38]   Sane H, Paranjape A, Nivins S. Correlation of testosterone levels with progression of amyotrophic lateral sclerosis: a cross section study. 2017
[39]   Rosen DR, Siddique T, Patterson D, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993, 362(6415): 59-62.
[40]   Boillée S, Vande Velde C, Cleveland DW. ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 2006, 52(1): 39-59.
[41]   Appel SH, Beers DR, Henkel JS. T cell-microglial dialogue in Parkinson's disease and amyotrophic lateral sclerosis: are we listening? Trends Immunol 2010, 31(1): 7-17.
[42]   Zhao WH, Xie WJ, Le WD, et al. Activated microglia initiate motor neuron injury by a nitric oxide and glutamate-mediated mechanism. J Neuropathol Exp Neurol 2004, 63(9): 964-977.
[43]   Burguillos MA, Deierborg T, Kavanagh E, et al. Caspase signalling controls microglia activation and neurotoxicity. Nature 2011, 472(7343): 319-324.
[44]   Ghoshal A, Das S, Ghosh S, et al. Proinflammatory mediators released by activated microglia induces neuronal death in Japanese encephalitis. Glia 2007, 55(5): 483-496.
[45]   Zhao WH, Beers DR, Appel SH. Immune-mediated mechanisms in the pathoprogression of amyotrophic lateral sclerosis. J Neuroimmune Pharmacol 2013, 8(4): 888-899.
[46]   Neher JJ, Neniskyte U, Zhao JW, et al. Inhibition of microglial phagocytosis is sufficient to prevent inflammatory neuronal death. J Immunol 2011, 186(8): 4973-4983.
[47]   Norden DM, Godbout JP. Review: microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathol Appl Neurobiol 2013, 39(1): 19-34.
[48]   Hu XM, Leak RK, Shi YJ, et al. Microglial and macrophage polarization—new prospects for brain repair. Nat Rev Neurol 2015, 11(1): 56-64.
[49]   Dupuis L, Dengler R, Heneka MT, et al. A randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis. PLoS One 2012, 7(6): e37885.
[50]   Smith SA, Miller RG, Murphy JR, et al. Treatment of ALS with high dose pulse cyclophosphamide. J Neurol Sci 1994, 124(): 84-87.
[51]   Brown RH Jr, Hauser SL, Harrington H, et al. Failure of immunosuppression with a 10- to 14-day course of high-dose intravenous cyclophosphamide to alter the progression of amyotrophic lateral sclerosis. Arch Neurol 1986, 43(4): 383-384.
[52]   Cudkowicz ME, Shefner JM, Schoenfeld DA, et al. Trial of celecoxib in amyotrophic lateral sclerosis. Ann Neurol 2006, 60(1): 22-31.
[53]   Stommel EW, Cohen JA, Fadul CE, et al. Efficacy of thalidomide for the treatment of amyotrophic lateral sclerosis: a phase II open label clinical trial. Amyotroph Lateral Scler 2009, 10(5/6): 393-404.
[54]   Gordon PH, Moore DH, Miller RG, et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol 2007, 6(12): 1045-1053.
[55]   Levine TD, Bowser R, Hank NC, et al. A pilot trial of pioglitazone HCl and tretinoin in ALS: cerebrospinal fluid biomarkers to monitor drug efficacy and predict rate of disease progression. Neurol Res Int 2012, 2012: 582075.
[56]   Xie J, March KL, Murphy MP. Bone marrow-derived cells: from the laboratory to the clinic. In Regenerative Medicine for Peripheral Artery Disease. Mohler ER, III, Annex BH, Eds. Amsterdam: Elsevier, 2016, pp. 27-42.
[57]   Challen GA, Little MH. A side order of stem cells: the SP phenotype. Stem Cells 2006, 24(1): 3-12.
[58]   Salem HK, Thiemermann C. Mesenchymal stromal cells: current understanding and clinical status. Stem Cells 2010, 28(3): 585-596.
[59]   Kucia MJ, Wysoczynski M, Wu W, et al. Evidence that very small embryonic-like stem cells are mobilized into peripheral blood. Stem Cells 2008, 26(8): 2083-2092.
[60]   Ji KH, Xiong J, Hu KM, et al. Simultaneous expression of Oct4 and genes of three germ layers in single cell-derived multipotent adult progenitor cells. Ann Hematol 2008, 87(6): 431-438.
[61]   Park C, Ma YD, Choi K. Evidence for the hemangioblast. Exp Hematol 2005, 33(9): 965-970.
[62]   Kucia M, Reca R, Jala VR, et al. Bone marrow as a home of heterogenous populations of nonhematopoietic stem cells. Leukemia 2005, 19(7): 1118-1127.
[63]   Yang B, Parsha K, Schaar K, et al. Various cell populations within the mononuclear fraction of bone marrow contribute to the beneficial effects of autologous bone marrow cell therapy in a rodent stroke model. Transl Stroke Res 2016, 7(4): 322-330.
[64]   Kim J, Hematti P. Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages. Exp Hematol 2009, 37(12): 1445-1453.
[65]   Hegyi B, K?rnyei Z, Ferenczi S, et al. Regulation of mouse microglia activation and effector functions by bone marrow-derived mesenchymal stem cells. Stem Cells Dev 2014, 23(21): 2600-2612.
[66]   Liu J, Hjorth E, Zhu M, et al. Interplay between human microglia and neural stem/progenitor cells in an allogeneic co-culture model. J Cell Mol Med 2013, 17(11): 1434-1443.
[67]   Yan K, Zhang R, Sun CM, et al. Bone marrow-derived mesenchymal stem cells maintain the resting phenotype of microglia and inhibit microglial activation. PLoS One 2013, 8(12): e84116.
[68]   Pastor D, Viso-León MC, Jones J, et al. Comparative effects between bone marrow and mesenchymal stem cell transplantation in GDNF expression and motor function recovery in a motorneuron degenerative mouse model. Stem Cell Rev Rep 2012, 8(2): 445-458.
[69]   Labouyrie E, Dubus P, Groppi A, et al. Expression of neurotrophins and their receptors in human bone marrow. Am J Pathol 1999, 154(2): 405-415.
[70]   Jones J, Jaramillo-Merchán J, Bueno C, et al. Mesenchymal stem cells rescue Purkinje cells and improve motor functions in a mouse model of cerebellar Ataxia. Neurobiol Dis 2010, 40(2): 415-423.
[71]   Auffray I, Chevalier S, Froger J, et al. Nerve growth factor is involved in the supportive effect by bone marrow-derived stromal cells of the factor-dependent human cell line UT-7. Blood 1996, 88(5): 1608-18.
[72]   Wang YM, Mao XO, Xie L, et al. Vascular endothelial growth factor overexpression delays neurodegeneration and prolongs survival in amyotrophic lateral sclerosis mice. J Neurosci 2007, 27(2): 304-307.
[73]   Cabanes C, Bonilla S, Tabares L, et al. Neuroprotective effect of adult hematopoietic stem cells in a mouse model of motoneuron degeneration. Neurobiol Dis 2007, 26(2): 408-418.
[74]   Suzuki M, McHugh J, Tork C, et al. GDNF secreting human neural progenitor cells protect dying motor neurons, but not their projection to muscle, in a rat model of familial ALS. PLoS One 2007, 2(8): e689.
[75]   Wang JP, Fu XJ, Jiang C, et al. Bone marrow mononuclear cell transplantation promotes therapeutic angiogenesis via upregulation of the VEGF-VEGFR2 signaling pathway in a rat model of vascular dementia. Behav Brain Res 2014, 265: 171-180.
[76]   Oosthuyse B, Moons L, Storkebaum E, et al. Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration. Nat Genet 2001, 28(2): 131-138.
[77]   Jin KL, Mao XO, Greenberg DA. Vascular endothelial growth factor: direct neuroprotective effect in in vitro ischemia. Proc Natl Acad Sci USA 2000, 97(18): 10242-10247.
[78]   Jin KL, Mao XO, Nagayama T, et al. Induction of vascular endothelial growth factor receptors and phosphatidylinositol 3'-kinase/Akt signaling by global cerebral ischemia in the rat. Neuroscience 2000, 100(4): 713-717.
[79]   Silverman WF, Krum JM, Mani N, et al. Vascular, glial and neuronal effects of vascular endothelial growth factor in mesencephalic explant cultures. Neuroscience 1999, 90(4): 1529-1541.
[80]   Carmeliet P, de Almodovar CR. VEGF ligands and receptors: implications in neurodevelopment and neurodegeneration. Cell Mol Life Sci 2013, 70(10): 1763-1778.
[81]   Ruiz de Almodovar C, Lambrechts D, Mazzone M, et al. Role and therapeutic potential of VEGF in the nervous system. Physiol Rev 2009, 89(2): 607-648.
[82]   Azzouz M, Ralph GS, Storkebaum E, et al. VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature 2004, 429(6990): 413-417.
[83]   Storkebaum E, Lambrechts D, Dewerchin M, et al. Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS. Nat Neurosci 2005, 8(1): 85-92.
[84]   Zheng CY, Nennesmo I, Fadeel B, et al. Vascular endothelial growth factor prolongs survival in a transgenic mouse model of ALS. Ann Neurol 2004, 56(4): 564-567.
[85]   Feng HL, Leng Y, Ma CH, et al. Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model. Neuroscience 2008, 155(3): 567-572.
[86]   Chen RW, Chuang DM. Long term lithium treatment suppresses p53 and Bax expression but increases Bcl-2 expression. A prominent role in neuroprotection against excitotoxicity. J Biol Chem 1999, 274(10): 6039-6042.
[87]   Shalbuyeva N, Brustovetsky T, Brustovetsky N. Lithium desensitizes brain mitochondria to calcium, antagonizes permeability transition, and diminishes cytochrome C release. J Biol Chem 2007, 282(25): 18057-18068.
[88]   Bachmann RF, Wang Y, Yuan PX, et al. Common effects of lithium and valproate on mitochondrial functions: protection against methamphetamine-induced mitochondrial damage. Int J Neuropsychopharmacol 2009, 12(6): 805-822.
[89]   Quiroz JA, Machado-Vieira R, Zarate CA Jr, et al. Novel insights into lithium's mechanism of action: neurotrophic and neuroprotective effects. Neuropsychobiology 2010, 62(1): 50-60.
[90]   Bosche B, Sch?fer M, Graf R, et al. Lithium prevents early cytosolic calcium increase and secondary injurious calcium overload in glycolytically inhibited endothelial cells. Biochem Biophys Res Commun 2013, 434(2): 268-272.
[91]   Ngok-Ngam P, Watcharasit P, Thiantanawat A, et al. Pharmacological inhibition of GSK3 attenuates DNA damage-induced apoptosis via reduction of p53 mitochondrial translocation and Bax oligomerization in neuroblastoma SH-SY5Y cells. Cell Mol Biol Lett 2013, 18(1): 58-74.
[92]   Feier G, Valvassori SS, Varela RB, et al. Lithium and valproate modulate energy metabolism in an animal model of mania induced by methamphetamine. Pharmacol Biochem Behav 2013, 103(3): 589-596.
[93]   Busceti CL, Biagioni F, Riozzi B, et al. Enhanced tau phosphorylation in the hippocampus of mice treated with 3,4-methylenedioxymethamphetamine (“Ecstasy”). J Neurosci 2008, 28(12): 3234-3245.
[94]   Fornai F, Longone P, Cafaro L, et al. Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 2008, 105(6): 2052-2057.
[95]   Harris VK, Yan QJ, Vyshkina T, et al. Clinical and pathological effects of intrathecal injection of mesenchymal stem cell-derived neural progenitors in an experimental model of multiple sclerosis. J Neurol Sci 2012, 313(1/2): 167-177.
[96]   Wu SF, Suzuki Y, Kitada M, et al. New method for transplantation of neurosphere cells into injured spinal cord through cerebrospinal fluid in rat. Neurosci Lett 2002, 318(2): 81-84.
[97]   Bai HL, Suzuki Y, Noda T, et al. Dissemination and proliferation of neural stem cells on the spinal cord by injection into the fourth ventricle of the rat: a method for cell transplantation. J Neurosci Methods 2003, 124(2): 181-187.
[98]   Fischer UM, Harting MT, Jimenez F, et al. Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev 2009, 18(5): 683-692.
[99]   Vasconcelos-dos-Santos A, Rosado-de-Castro PH, Lopes de Souza SA, et al. Intravenous and intra-arterial administration of bone marrow mononuclear cells after focal cerebral ischemia: Is there a difference in biodistribution and efficacy? Stem Cell Res 2012, 9(1): 1-8.
[100]   Sadan O, Melamed E, Offen D. Bone-marrow-derived mesenchymal stem cell therapy for neurodegenerative diseases. Expert Opin Biol Ther 2009, 9(12): 1487-1497.
[101]   Pastor D, Viso-León MC, Botella-López A, et al. Bone marrow transplantation in hindlimb muscles of motoneuron degenerative mice reduces neuronal death and improves motor function. Stem Cells Dev 2013, 22(11): 1633-1644.
[102]   Corti S, Locatelli F, Donadoni C, et al. Wild-type bone marrow cells ameliorate the phenotype of SOD1-G93A ALS mice and contribute to CNS, heart and skeletal muscle tissues. Brain 2004, 127(Pt 11): 2518-2532.
[103]   Gubert F, Bonacossa-Pereira I, Decotelli AB, et al. Bone-marrow mononuclear cell therapy in a mouse model of amyotrophic lateral sclerosis: Functional outcomes from different administration routes. Brain Res 2019, 1712: 73-81.
[104]   Gubert F, Decotelli AB, Bonacossa-Pereira I, et al. Intraspinal bone-marrow cell therapy at pre- and symptomatic phases in a mouse model of amyotrophic lateral sclerosis. Stem Cell Res Ther 2016, 7: 41.
[105]   R. Martinez H, Gómez-Almaguer D, Jaime-Pérez JC, et al. Intrathecal delivery of bone marrow stem cells in ALS: A preliminary report. Trends in Transplant, 2017 10(1): 1-6.
[106]   Deda H, Inci MC, Kürek?i AE, et al. Treatment of amyotrophic lateral sclerosis patients by autologous bone marrow-derived hematopoietic stem cell transplantation: a 1-year follow-up. Cytotherapy 2009, 11(1): 18-25.
[107]   Ruiz-López FJ, Guardiola J, Izura V, et al. Breathing pattern in a phase I clinical trial of intraspinal injection of autologous bone marrow mononuclear cells in patients with amyotrophic lateral sclerosis. Respir Physiol Neurobiol 2016, 221: 54-58.
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[3] Xinyu Wang, Nan Sun, Xiangqi Meng, Meng Chen, Chuanlu Jiang, Jinquan Cai. Review of clinical nerve repair strategies for neurorestoration of central nervous system tumor damage[J]. Journal of Neurorestoratology, 2020, 8(3): 172-181.
[4] Hongyun Huang, Lin Chen, Gengsheng Mao, Hari Shanker Sharma. Clinical neurorestorative cell therapies: Developmental process, current state and future prospective[J]. Journal of Neurorestoratology, 2020, 8(2): 61-82.
[5] Nanlin Shi, Liping Wang, Yonghao Chen, Xinyi Yan, Chen Yang, Yijun Wang, Xiaorong Gao. Steady-state visual evoked potential (SSVEP)-based brain–computer interface (BCI) of Chinese speller for a patient with amyotrophic lateral sclerosis: A case report[J]. Journal of Neurorestoratology, 2020, 8(1): 40-52.
[6] Miaomiao Zhuang, Qingheng Wu, Feng Wan, Yong Hu. State-of-the-art non-invasive brain–computer interface for neural rehabilitation: A review[J]. Journal of Neurorestoratology, 2020, 8(1): 12-25.
[7] Xiaoling Guo, Xin Wang, Yan Li, Bo Zhou, Weidong Chen, Lihua Ren. Olfactory ensheathing cell transplantation improving cerebral infarction sequela: a case report and literature review[J]. Journal of Neurorestoratology, 2019, 7(2): 82-88.
[8] Gengsheng Mao, Yunliang Wang, Xiaoling Guo, Jun Liu, Zuncheng Zheng, Lin Chen. Neurorestorative effect of olfactory ensheathing cells and Schwann cells by intranasal delivery for patients with ischemic stroke: design of a multicenter randomized double-blinded placebo-controlled clinical study[J]. Journal of Neurorestoratology, 2018, 6(1): 74-80.
[9] Andrey S. Bryukhovetskiy. Translational experience of 28 years of use of the technologies of regenerative medicine to treat complex consequences of the brain and spinal cord trauma: Results, problems and conclusions[J]. Journal of Neurorestoratology, 2018, 6(1): 99-114.
[10] Hongyun Huang, Hari Shanker Sharma, Lin Chen, Ali Otom, Ziad M. Al Zoubi, Hooshang Saberi, Dafin F. Muresanu, Xijing He. Review of clinical neurorestorative strategies for spinal cord injury: Exploring history and latest progresses[J]. Journal of Neurorestoratology, 2018, 6(1): 171-178.
[11] Hongyun Huang, Lin Chen, Qingyan Zou, Fabin Han, Tiansheng Sun, Gengsheng Mao, Xijing He. Clinical cell therapy guidelines for neurorestoration (China version 2016)[J]. Journal of Neurorestoratology, 2017, 5(1): 39-46.
[12] Alok Sharma, Tongchao Geng, Hemangi Sane, Pooja Kulkarni. Clinical neurorestorative progresses in cerebral palsy[J]. Journal of Neurorestoratology, 2017, 5(1): 51-57.
[13] Yaping Feng, Tiansheng Sun, Lin Chen, Jiaxin Xie, Zhicheng Zhang, Hongyun Huang, Xijing He. Clinical therapeutic guideline for neurorestoration in spinal cord injury (Chinese version 2016)[J]. Journal of Neurorestoratology, 2017, 5(1): 73-83.
[14] Alok Sharma, Ziad M Al Zoubi. Rethinking on ethics and regulations in cell therapy as part of neurorestoratology[J]. Journal of Neurorestoratology, 2016, 4(1): 1-14.
[15] Adeeb Al-Zoubi, Feras Altwal, Farah Khalifeh, Jamil Hermas, Ziad Al-Zoubi, Emad Jafar, Mohammed El-Khateeb. Ex vivo differentiation of human bone marrow-derived stem cells into neuronal cell-like lineages[J]. Journal of Neurorestoratology, 2016, 4(1): 35-44.