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Journal of Neurorestoratology  2019, Vol. 7 Issue (2): 89-100    doi: 10.26599/JNR.2019.9040010
Research Article     
Intranasal delivery of M2 macrophage-derived soluble products reduces neuropsychological deficit in patients with cerebrovascular disease: a pilot study
Ekaterina Shevela(✉), Marina Davydova, Natalia Starostina, Alexandra Yankovskaya, Alexandr Ostanin, Elena Chernykh
Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
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Abstract  Objective:

We assessed the safety and clinical effectiveness of intranasal therapy with M2 macrophage-derived soluble products (M2-SPs) for treating patients with cerebrovascular disease (CVD).

Materials and methods:

The protocol of the study was registered at www.ClinicalTrails.gov (NCT02957123). The study group comprised 30 patients with chronic CVD. Neurological status was examined before therapy and at 1- and 6-month follow–up. Concentrations of 32 cytokines in the blood serum were evaluated before and 1 month after therapy onset. Neurological assessment was conducted with the following scales: Subjective Assessment of Clinical (neurological) Symptoms (SACS), Hospital Anxiety and Depression Scale (HADS), Functional Mobility Assessment in Eldery Patients (FMA), and Montreal Cognitive Assessment (MoCa).

Results:

M2-SPs treatment (once daily for 28~30 days) was found to be safe and well tolerated. Neuropsychological improvements showed the amelioration of neurological symptoms, reduction in anxiety and depression levels, improvement in balance and gait ability as well as cognitive functions. Clinical effects could be detected at the end of treatment course and was stable during 6-month follow-up. Blood serum cytokine evaluation demonstrated diminished baseline levels of many cytokines including those with neurotrophic activity (brain-derived neurotrophic factor, BDNF; hepatocyte growth factor, HGF; migration inhibitory factor, MIF). Upon treatment, most pronounced clinical responses were observed in patients with most severe cytokine deficiency and post-therapy normalization of MIF and HGF levels.

Conclusion:

Intranasal therapy with M2-SPs is safe and according to preliminary data reduces neuropsychological deficit in patients with chronic CVD. The positive effect of M2-SPs treatment seems to be HGF- and MIF-dependent.



Key wordschronic cerebrovascular disease      intranasal therapy      M2-macrophages      cytokines      neurological improvement     
Received: 21 April 2019      Published: 22 July 2019
Corresponding Authors: Ekaterina Shevela   
Cite this article:

Ekaterina Shevela, Marina Davydova, Natalia Starostina, Alexandra Yankovskaya, Alexandr Ostanin, Elena Chernykh. Intranasal delivery of M2 macrophage-derived soluble products reduces neuropsychological deficit in patients with cerebrovascular disease: a pilot study. Journal of Neurorestoratology, 2019, 7: 89-100.

URL:

http://jnr.tsinghuajournals.com/10.26599/JNR.2019.9040010     OR     http://jnr.tsinghuajournals.com/Y2019/V7/I2/89

No.Age/SexDiagnosisNIHSS scorePost-stroke periodRisk factors
175/FChronic CVD421 yearsSmoking, HT
257/MChronic CVD18 yearsSmoking, HT
362/MChronic CVD75 monthsObesity, DM, HT
436/MChronic CVD920 monthsHT
567/FChronic CVDObesity
654/MChronic CVDCHD, HT, Smoking
755/FChronic CVDObesity, HT
868/MChronic CVDNeuroinfection, HT
976/MChronic CVD32 monthsCHD, HT
1066/MChronic CVDHT, CHD, Obesity
1134/FChronic CVDHT, CHD
1258/FChronic CVD13 monthsHT
1377/MChronic CVDHT, Obesity, DM
1468/MChronic CVDCHD, HT
1563/FChronic CVDHT
1669/FChronic CVDHT, Obesity
1781/FChronic CVDCHD, HT
1849/FChronic CVD1122 monthsHT
1955/FChronic CVD115 monthsHT
2077/FChronic CVDHT
2154/MChronic CVDHT, Smoking
2276/FChronic CVDHT, DM
2364/FChronic CVDObesity
2461/FChronic CVD09 yearsHT, DM
2557/FChronic CVD032 monthsHT
2675/MChronic CVDSmoking, HT, DM
2755/FChronic CVDHT
2866/FChronic CVDHT
2970/FChronic CVD98 monthsDM
3056/FChronic CVD124 monthsObesity
Table 1Baseline characteristics of patients.
Score, MeIQRSymptom frequency
Anxiety/Depression (HADS > 7)16.511–2126/30 (86.7%)
Impaired stability/Gait (FMA ≤ 38)3025–3528/30 (93.3%)
Cognitive impairments (MoCa < 26)2422–2419/30 (63.3%)
Neurological symptoms (SACS ≥ 6):14.511–1830/30 (100%)
Headache26/30 (86.7%)
Dizziness26/30 (86.7%)
Gait disturbance25/30 (83.3%)
Weakness in the limbs9/30 (30%)
Sensation10/30 (33.3%)
Spasticity5/30 (16.7%)
Speech disorders8/30 (26.7%)
Visual impairment2/30 (6.7%)
Tinnitus18/30 (60%)
Tremor11/30 (36.7%)
Cognitive impairments27/30 (90%)
Dysfunction of the pelvic organs1/30 (3.3%)
Fatigue/Asthenia30/30 (100%)
Emotional lability20/30 (66.7%)
Paroxysms6/30 (20%)
Table 2Neurological examination of patients at baseline.
Baseline1 month6 months
SACS14.5 (11–18)8 (5–14)**7 (4–12)**,#
HADS16.5 (11–21)9 (6–14)**8 (5–13)**
FMA30 (25–35)36 (33–38)**36 (34–38) **,#
MoCa24 (22–24)28 (26–29)**28 (26–29)**
Table 3Neurological examination of patients at baseline, 1 and 6 months after the therapy onset.
Subgroup 1Subgroup 2
Before1 month6 monthsBefore1 month6 months
SACS14 (11–17)7.5*** (4–10)6.5*** (3.5–10)14 (11–22)10.5* (7–22)11* (7–19)
HADS15.5 (9–21)8*** (5–10.5)5.5*** (4–13)13 (11–18)10* (6–15)9 (5–15)
FMA30 (27–35)36*** (33–38)37*** (35–39)27 (22–34)32.5 (26–38)36 (29–36)
MoCa24 (23–25)28** (27–29)28** (27–29)23.5 (22–24)27 (24–29)27 (24–29)
Table 4Neurological examination of patients with strong (Subgroup 1) or moderate (Subgroup 2) response on intranasal therapy with M2-SPs.
Cytokines (pg/mL)Control (n = 10)Before therapy (n = 15)After 1 month (n = 15)pp
1232 vs 13 vs 1
Pro-inflammatory and pro-apoptotic cytokinesIL-184.5 (1.0–10.2)1.9 (1.0–3.2)3.2 (0.6–5.5)
MIF200 (92–261)91 (68–157) *179 (120–371)0.0460.8
IFN-α228 (20–57)29 (9–37)23 (6–34)
TNF-alpha73 (68–134)71 (6–111)61 (7–241)
TRAIL32 (26–47)22 (9–31) *15 (1.5–44) *0.020.03
Th1 and Th2 cytokinesIL-218 (16–25)12 (1.5–21)11 (1.5–52)
IL-2Rα27 (23–57)19 (6–28) *18 (3–24) *0.020.02
IFN-γ464 (200–774)340 (44–564)260 (76–1280)
IL-418 (14–27)17 (6–22)17 (7–38)
IL-628 (24–61)23 (4–26) *12 (4–96)0.0490.37
IL-1015 (12–21)7.0 (2–12) *5.0 (2–41)0.050.62
Neurotrophic and pro-angiogenic factorsHGF60 (33–121)14 (4–33) **19 (5–71) *0.00090.05
BDNF12570 (10610–14000)6740 (3600–9410) **8160 (2540–10390) *0.010.02
IGF-1 (нг/мл)125 (112–140)107 (97–131)114 (89–196)
β-NGF36 (22–60)36 (18–44)27 (13–47)
Haematopoietic factorsSCF43 (33–48)29 (19–43)32 (24–38)
IL-364 (59–92)59 (13–89)31 (13–86)
GM-CSF63 (60–104)37 (5–86)35 (5–165)
ChemokinesIL-16154 (150–240)104 (10–147) **87 (7–210)0.0070.12
CTACK232 (202–374)128 (98–194) *240 (94–294)0.040.37
GRO-α39 (34–69)17 (4–34) **4.0 (3–38) *0.0030.04
IL-858 (54–72)39 (6–72)44 (15–127)
MCP-332 (29–69)16 (2–39)20 (2–45)
MCP-1170 (140–200)125 (79–214)129 (84–191)
MIG178 (113–390)164 (5–414)78 (5–363)
SDF-1alpha265 (240–366)200 (126–309)168 (74–315)
Table 5Cytokine concentrations in patient blood serum before and 1 month after the beginning of intranasal treatment with М2-SPs.
Cytokines (pg/mL)Control (n = 10)Subgroup 1 (n = 9)Subgroup 2 (n = 6)p
*#*
1232 vs 12 vs 33 vs 1
MIF200 (92–261)90 (71–157)86 (65–100)0.07 0.12
TRAIL32 (26–47)22 (9–29) *24 (14–31)0.03 0.10
IL-218 (16–25)6.5 (1.5–12) **, #19 (16–33)0.0090.050.66
IL-2Rα27 (23–57)18 (6–28) *22 (8–24)0.04 0.06
IFN-γ464 (200–774)120 (38–340) *, #526 (360–930)0.050.040.62
IL-628 (24–61)4.0 (4–25) **, #29 (23–76)0.0040.040.99
IL-1015 (12–21)2.5 (2–10) *12 (7–27)0.010.120.66
HGF60 (33–121)17 (5–30) **5.0 (4–33) **0.0040.340.006
BDNF12570 (10610–14000)7250 (2100–9410) *6560 (5960–8120)0.01 0.10
SCF43 (33–48)27 (20–43)40 (13–42)0.06 0.23
GM-CSF63 (60–104)17 (4.5–37) *, #72 (57–146)0.020.050.91
IL-16154 (150–240)104 (10–125) *138 (61–147) *0.02 0.03
CTACK232 (202–374)112 (5–182) *157 (102–232)0.03 0.28
GRO-α39 (34–69)4.0 (4–30) **20 (3–47) *0.0030.720.05
IL-858 (54–72)25 (6–47) *62 (39–120)0.020.110.91
MCP-1170 (140–200)121 (68–162)156 (122–214)0.06 0.74
Table 6Baseline cytokine level in patients with strong (Subgroup 1) or moderate (Subgroup 2) response on intranasal therapy with M2-SPs.
Fig. 1The concentrations of MIF (A) and HGF (B) in blood serum of patients with strong and moderate response to the intranasal M2-SP therapy before M2-SP administration and 1 month after the therapy onset. The data are presented as medians and IQR. Significance of differences is evaluated with Fishes’s exact test (pFET).
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