Neuroprotective Properties of Mildronate, a Small Molecule, in a Rat Model of Parkinson’s Disease

Abstract

Previously, we have found that mildronate [3-(2,2,2-trimethylhydrazinium) propionate dihydrate], a small molecule with charged nitrogen and oxygen atoms, protects mitochondrial metabolism that is altered by inhibitors of complex I and has neuroprotective effects in an azidothymidine-neurotoxicity mouse model. In the present study, we investigated the effects of mildronate in a rat model of Parkinson’s disease (PD) that was generated via a unilateral intrastriatal injection of the neurotoxin 6-hydroxydopamine (6-OHDA). We assessed the expression of cell biomarkers that are involved in signaling cascades and provide neural and glial integration: the neuronal marker TH (tyrosine hydroxylase); ubiquitin (a regulatory peptide involved in the ubiquitin-proteasome degradation system); Notch-3 (a marker of progenitor cells); IBA-1 (a marker of microglial cells); glial fibrillary acidic protein, GFAP (a marker of astrocytes); and inducible nitric oxide synthase, iNOS (a marker of inflammation). The data show that in the 6-OHDA-lesioned striatum, mildronate completely prevented the loss of TH, stimulated Notch-3 expression and decreased the expression of ubiquitin, GFAP and iNOS. These results provide evidence for the ability of mildronate to control the expression of an array of cellular proteins and, thus, impart multi-faceted homeostatic mechanisms in neurons and glial cells in a rat model of PD. We suggest that the use of mildronate provides a protective effect during the early stages of PD that can delay or halt the progression of this neurodegenerative disease.

Neuroprotective Effects of A Standardized Flavonoid Extract of Safflower Against Neurotoxin-Induced Cellular and Animal Models of Parkinson’s Disease

“…In the present study, we found that 6-OHDA treatment increased the numbers of reactive astrocytes, which agrees with previous findings 4 5 6 . Astrogliosis is a key player in neuroinflammatory responses and has long been a pathological observation in PD 4 5 6 . However, astrogliosis is the subject of much debate.…”

“…However, astrogliosis is the subject of much debate. On one hand, the activated astrocytes might produce neurotrophic factors and stimulate microglial cells, resulting in the induction of dopaminergic neurons 4 . On the other hand, sustained inflammatory astrogliosis might result in the secretion of a broad array of neurotoxic molecules, including proinflammatory cytokines, chemokines, prostaglandins and large amounts of reactive oxygen and nitrogen species that contribute to the progression of disease states.…”

“…In rats, the unilateral intracerebral injection of 6-hydroxydopamine (6-OHDA) results in a selective degeneration of dopaminergic neurons, and this is a widely used animal model of PD. 6-OHDA induces a neurodegenerative process in the nigrostriatal system through the inhibition of mitochondrial complex function, which can lead to the induction of oxidative stress, inflammation 4 5 6 , abnormal protein aggregation 7 8 , elevated iron levels 9 and ultimately cell death.…”

Neuroprotective effect of combined therapy with hyperbaric oxygen and madopar on 6-hydroxydopamine-induced Parkinson’s disease in rats

“…According to the method of previous study [21,22,34], the waxed specimens were incubated with primary antibody (tyrosine hydroxylase (TH) antibody, or GFAP antibody, or Bax antibody, or Bcl-2 antibody, 1:100 dilution, Zhongshan Goldenbridge Biological Technology, Beijing, China) overnight at 4 • C, washed three times with 0.1 mol/L PBS for 3 min each, and incubated with biotinylated goat antirabbit immunoglobulin G (Zhongshan Goldenbridge Biological Technology, Beijing, China) at 30 • C for 25 min. After washing three times with 0.1 mol/L PBS for 3 min each, the specimens were incubated with a streptavidin-biotin complex at 30 • C for 20 min.…”

Mildronate improves cognition and reduces amyloid‐β pathology in transgenic Alzheimer's disease mice

“…In previous studies, mildronate has been demonstrated to have neuroprotective properties in the mouse azidothymidine neurotoxicity model by suppressing inflammation and apoptotic processes in the brain, i.e., reduced lymphocyte infiltration in the brain and decreased activated caspase 3 levels (Pupure et al, ). In the Parkinson's disease 6‐hydroxydopamine rat model (Klusa et al, ; Isajevs et al, ), it reduced proteins related to inflammation, such as glial; fibrillary acidic protein (GFAP), inducible NO synthase (iNOS), and ionized calcium‐binding adapter molecule 1 (Iba‐1). Furthermore, mildronate treatment effectively normalized neurological disturbances and reduced the infarct size in the ischemic stroke endothelin‐1 model in rats (Rumaks et al, ).…”