PMID- 35401218
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220413
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 13
DP  - 2022
TI  - Combination Therapy of Alpha-Lipoic Acid, Gliclazide and Ramipril Protects 
      Against Development of Diabetic Cardiomyopathy via Inhibition of TGF-beta/Smad 
      Pathway.
PG  - 850542
LID - 10.3389/fphar.2022.850542 [doi]
LID - 850542
AB  - Background: Diabetic cardiomyopathy (DCM) is a major long-term complication of 
      diabetes mellitus, accounting for over 20% of annual mortality rate of diabetic 
      patients globally. Although several existing anti-diabetic drugs have improved 
      glycemic status in diabetic patients, prevalence of DCM is still high. This study 
      investigates cardiac effect of alpha-lipoic acid (ALA) supplementation of 
      anti-diabetic therapy in experimental DCM. Methods: Following 12 h of overnight 
      fasting, 44 male Sprague Dawley rats were randomly assigned to two groups of 
      healthy control (n = 7) and diabetic (n = 37) groups, and fasting blood glucose 
      was measured. Type 2 diabetes mellitus (T2DM) was induced in diabetic group by 
      intraperitoneal (i.p.) administration of nicotinamide (110 mg/kg) and 
      streptozotocin (55 mg/kg). After confirmation of T2DM on day 3, diabetic rats 
      received monotherapies with ALA (60 mg/kg; n = 7), gliclazide (15 mg/kg; n = 7), 
      ramipril (10 mg/kg; n = 7) or combination of the three drugs (n = 7) for 6 weeks 
      while untreated diabetic rats received distilled water and were used as diabetic 
      control (n = 9). Rats were then sacrificed, and blood, pancreas and heart tissues 
      were harvested for analyses using standard methods. Results: T2DM induction 
      caused pancreatic islet destruction, hyperglycemia, weight loss, high relative 
      heart weight, and development of DCM, which was characterized by myocardial 
      degeneration and vacuolation, cardiac fibrosis, elevated cardiac damage markers 
      (plasma and cardiac creatine kinase-myocardial band, brain natriuretic peptide 
      and cardiac troponin I). Triple combination therapy of ALA, gliclazide and 
      ramipril preserved islet structure, maintained body weight and blood glucose 
      level, and prevented DCM development compared to diabetic control (p < 0.001). In 
      addition, the combination therapy markedly reduced plasma levels of inflammatory 
      markers (IL-1beta, IL-6 and TNF-alpha), plasma and cardiac tissue malondialdehyde, 
      triglycerides and total cholesterol while significantly increasing cardiac 
      glutathione and superoxide dismutase activity and high-density 
      lipoprotein-cholesterol compared to diabetic control (p < 0.001). 
      Mechanistically, induction of T2DM upregulated cardiac expression of TGF-beta1, 
      phosphorylated Smad2 and Smad3 proteins, which were downregulated following 
      triple combination therapy (p < 0.001). Conclusion: Triple combination therapy of 
      ALA, gliclazide and ramipril prevented DCM development by inhibiting TGF-beta1/Smad 
      pathway. Our findings can be extrapolated to the human heart, which would provide 
      effective additional pharmacological therapy against DCM in T2DM patients.
CI  - Copyright (c) 2022 Dugbartey, Wonje, Alornyo, Robertson, Adams, Boima and Mensah.
FAU - Dugbartey, George J
AU  - Dugbartey GJ
AD  - Department of Pharmacology and Toxicology, School of Pharmacy, College of Health 
      Sciences, University of Ghana, Accra, Ghana.
FAU - Wonje, Quinsker L
AU  - Wonje QL
AD  - Department of Pharmacology and Toxicology, School of Pharmacy, College of Health 
      Sciences, University of Ghana, Accra, Ghana.
FAU - Alornyo, Karl K
AU  - Alornyo KK
AD  - Department of Pharmacology and Toxicology, School of Pharmacy, College of Health 
      Sciences, University of Ghana, Accra, Ghana.
FAU - Robertson, Louis
AU  - Robertson L
AD  - Department of Pharmacology and Toxicology, School of Pharmacy, College of Health 
      Sciences, University of Ghana, Accra, Ghana.
FAU - Adams, Ismaila
AU  - Adams I
AD  - Department of Pharmacology and Toxicology, School of Pharmacy, College of Health 
      Sciences, University of Ghana, Accra, Ghana.
FAU - Boima, Vincent
AU  - Boima V
AD  - Department of Medicine and Therapeutics, University of Ghana Medical School, 
      College of Health Sciences, University of Ghana, Accra, Ghana.
FAU - Mensah, Samuel D
AU  - Mensah SD
AD  - Department of Pharmacology and Toxicology, School of Pharmacy, College of Health 
      Sciences, University of Ghana, Accra, Ghana.
LA  - eng
PT  - Journal Article
DEP - 20220321
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC8988231
OTO - NOTNLM
OT  - alpha-lipoic acid (ALA)
OT  - anti-diabetic therapy
OT  - diabetic cardiomyopathy (DCM)
OT  - triple combination therapy
OT  - type 2 diabetes mellitus (T2DM)
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2022/04/12 06:00
MHDA- 2022/04/12 06:01
PMCR- 2022/03/21
CRDT- 2022/04/11 05:27
PHST- 2022/01/07 00:00 [received]
PHST- 2022/02/21 00:00 [accepted]
PHST- 2022/04/11 05:27 [entrez]
PHST- 2022/04/12 06:00 [pubmed]
PHST- 2022/04/12 06:01 [medline]
PHST- 2022/03/21 00:00 [pmc-release]
AID - 850542 [pii]
AID - 10.3389/fphar.2022.850542 [doi]
PST - epublish
SO  - Front Pharmacol. 2022 Mar 21;13:850542. doi: 10.3389/fphar.2022.850542. 
      eCollection 2022.