PMID- 36278164
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20221025
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 13
DP  - 2022
TI  - Investigation of Natural Compounds for Therapeutic Potential in 
      Streptozotocin-induced Diabetic Neuroinflammation and Neuropathic Pain.
PG  - 1019033
LID - 10.3389/fphar.2022.1019033 [doi]
LID - 1019033
AB  - Diabetic neuropathy (DN) is a serious microvascular complication of diabetes 
      mellitus (DM) that impacts the nervous system. Several risk factors are involved 
      in the progression and maintenance of DN-associated pain, such as higher 
      expression of various inflammatory mediators, e.g., tumor necrotic factor-alpha 
      (TNF-alpha), nuclear factor-kappa B (NF-kappaB), and cyclo-oxygenase-2 (COX-2). The 
      present research explores the neuroprotective potential of natural isolates, 
      including berbamine, bergapten, and carveol, on the DM-induced neuroinflammation 
      and neurodegeneration that cause neuropathic pain. The study utilized 
      computerized techniques, including computational analysis (a docking assay and a 
      molecular dynamic simulation) before moving to in vivo protocols. Diabetic 
      neuropathy was induced by intraperitonial injection (IP) of streptozotocin 
      (65 mg/kg), and the animal subjects (rats) were kept for 4 weeks for the 
      development of DN. Once diabetic neuropathy was confirmed, the subjects were 
      treated with berbamine, bergapten, and carveol until the sixth week (i.e., 
      2 weeks of treatment). At the sixth week, the rats were sacrificed, and the 
      sciatic nerve and spinal cord of each was collected for further molecular 
      investigation. Docking and a molecular dynamic simulation (MDS) delivered the 
      information that the natural compounds (berbamine, bergapten, and carveol) were 
      interacting with the selected target protein (i.e., mitogen-activated protein 
      kinase). After IP, it was found that berbamine, bergapten, and carveol had 
      ameliorated mechanical allodynia and thermal hyperalgesia by the 28th day of the 
      study (2 weeks after treatment) without affecting blood glucose levels. 
      Berbamine, bergapten, and carveol markedly elevated the levels of glutathione 
      (GSH) and glutathione s-transferase (GST), in both the sciatic nerve and spinal 
      cord, and also reduced lipid peroxidase (LPO) and nitric oxide (NO). The 
      abovementioned natural isolates reduced pathologic alterations provoked through 
      DN, a finding confirmed through histopathological assays (hematoxylin and eosin 
      staining and immuno-histochemical analysis). Treatment down regulated higher 
      expressions of the inflammatory mediatorcyclooxygenase-2 (COX-2), tumor necrosis 
      factor-alpha (TNF-alpha), and nuclear factor kappa B (NF-kappaB), as confirmed by ELISA and 
      polymerase chain reaction (PCR). The outcomes of berbamine, bergapten, and 
      carveol are compared with those of pregabalin as a positive control group. 
      Compared to pregabalin, treatment with the aforementioned three natural compounds 
      improved nociception and reduced hyperalgesic effects, and consequently reduced 
      pain perception and inflammation. Our results suggest the mechanism for the 
      neuro-protective impact of berbamine, bergapten, and carveol might possibly be 
      arbitrated via COX-2, TNF-alpha, and NF-kappaB, and regulated by mitogen-activated 
      protein kinase, ultimately ameliorating STZ-provoked, DM-induced 
      neuroinflammation and neurodegeneration, and associated neuropathic pain.
CI  - Copyright (c) 2022 Faheem, Khan, Shah and Li.
FAU - Faheem, Muhammad
AU  - Faheem M
AD  - Riphah Institute of Pharmaceutical Sciences, Riphah International University, 
      Islamabad, Pakistan.
FAU - Khan, Arif-Ullah
AU  - Khan AU
AD  - Riphah Institute of Pharmaceutical Sciences, Riphah International University, 
      Islamabad, Pakistan.
FAU - Shah, Fawad Ali
AU  - Shah FA
AD  - Riphah Institute of Pharmaceutical Sciences, Riphah International University, 
      Islamabad, Pakistan.
FAU - Li, Shupeng
AU  - Li S
AD  - State Key Laboratory of Oncogenomics, School of Chemical Biology and 
      Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, China.
LA  - eng
PT  - Journal Article
DEP - 20221005
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC9581174
OTO - NOTNLM
OT  - ELISA
OT  - PCR
OT  - diabetic neuroinflammation
OT  - molecular dynamic simulation
OT  - natural compounds
OT  - neuropathic pain
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- 2022/10/25 06:00
MHDA- 2022/10/25 06:01
PMCR- 2022/10/05
CRDT- 2022/10/24 04:45
PHST- 2022/08/14 00:00 [received]
PHST- 2022/09/02 00:00 [accepted]
PHST- 2022/10/24 04:45 [entrez]
PHST- 2022/10/25 06:00 [pubmed]
PHST- 2022/10/25 06:01 [medline]
PHST- 2022/10/05 00:00 [pmc-release]
AID - 1019033 [pii]
AID - 10.3389/fphar.2022.1019033 [doi]
PST - epublish
SO  - Front Pharmacol. 2022 Oct 5;13:1019033. doi: 10.3389/fphar.2022.1019033. 
      eCollection 2022.