Cerebrolysin protects against rotenone-induced oxidative stress and neurodegeneration

Abstract

Abstract:We investigated the effect of cerebrolysin, a peptide mixture used for promoting memory and recovery from cerebral stroke, on the development of oxidative stress and nigrostriatal cell injury induced by rotenone administration in rats. Rotenone 1.5 mg/kg was given subcutaneously three times weekly either alone or in combination with cerebrolysin at 21.5, 43, or 86 mg/kg. Rats were euthanized 14 days after starting the rotenone injection. Lipid peroxidation (malondialdehyde), reduced glutathione (GSH), nitric oxide (nitrite) concentrations, paraoxonase 1 (PON1), and acetylcholinesterase (AChE) activities -as well as the monocyte chemoattractant protein-1 (MCP-1) and the antiapoptotic protein Bcl-2 -were measured in the brain. Histopathology, tyrosine hydroxylase, inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), and cleaved caspase-3 immunohistochemistry were also performed. Rotenone caused a significantly elevated oxidative stress and proinflammatory response in the different brain regions. Malondialdehyde and nitric oxide concentrations were significantly increased, while GSH markedly decreased in the cerebral cortex, striatum, hippocampus, and in the rest of the brain. PON1 and AChE activities significantly decreased with respect to the control levels after rotenone application. Striatal Bcl-2 was significantly decreased while MCP-1 increased following rotenone injection. Rotenone caused prominent iNOS, TNF-α, and caspase-3 immunostaining in the striatum and resulted in markedly decreased tyrosine hydroxylase immunoreactivity in the substantia nigra and striatum. Cerebrolysin coadministered with rotenone decreased lipid peroxidation, increased GSH, and inhibited the elevation of nitric oxide induced by rotenone. Cerebrolysin also decreased the rotenone-induced decline in the PON1 and AChE activities and the rotenone-mediated changes in the striatal Bcl-2 and MCP-1 levels. The drug reduced iNOs, TNF-α, and caspase 3 expressions and increased the tyrosine hydroxylase immunoreactivity in the striatum. Cerebrolysin markedly prevented the development of neuronal damage in the cortex and striatum. These data suggest that cerebrolysin may have potential therapeutic effect in Parkinson's disease.

Neuroprotection by Mast Cell Stabilizers and Histamine H1 Receptor Blockade in Rotenone-Induced Oxidative Stress and Nigrostriatal Damage

“…Moreover, and in consistence with our previous findings [29], we showed here that rotenone was capable of inhibiting the activity of PON1 in the different brain regions. The PON1 enzyme is involved in the hydrolysis of the active metabolites of a number of organophosphate insecticides (such as diazoxon, FIGURE 6.…”

“…Consistent with previous observations [29], rotenone exposure resulted in increased nitric oxide levels in the brain. Excess nitric oxide produced by the inducible form of nitric oxide synthase during toxic and inflammatory conditions has been shown to cause neurotoxicity and induce apoptotic cell death [30] Our findings thus confirmed previous studies suggesting oxidative stress and nitric oxide formation as contributing factors to rotenone-induced neurodegeneration [29,31,32]. In this context, it is noteworthy that the ability of rotenone to cause neuronal death in vitro could be prevented by the chainbreaking antioxidant -tocopherol [31] or by Nacetyl-cysteine, a glutathione precursor [32].…”

Neuroprotection by Montelukast against Rotenone-Induced Rat Brain Damage

“…Studies indicated that rotenone induces apoptotic cell death [42,47]. Strong cleaved caspase-3 immunoreactivity was observed in the striatum, substantia nigra, and cerebral cortex while the antiapoptotic protein Bcl-2 decreased in the striatum of rotenone-treated rodents [38,39,48]. It has also been shown that cells that are transduced with Ndi1 (nicotinamide-adenine dinucleotide-ubiquinone oxidoreductase) of Saccharomyces cerevisiae which replaces complex I were resistant to rotenone neurotoxicity [49].…”

“…The increase in brain nitric oxide is also likely to contribute to the rotenone neurotoxicity [27]. The neurotoxin has been demonstrated to increase the expression of the inducible form of nitric oxide synthase (iNOS) in the striatum and substantia nigra [37,48]. This enzyme is responsible for the excessive and prolonged release of nitric oxide by microglia and astrocytes observed during inflammation and under toxic conditions [50].…”

“…to inhibit acetylcholinesterase (AChE) activity in the cerebral cortex of injected rats [38,48]. This decrease in the activity of cholinesterases could be due to damage to cholinergic neurons and/or direct enzyme inhibition by the toxicant and is likely to contribute to the development of motor manifestations in response to rotenone administration.…”