Abstract
Stroke is a leading cause of death worldwide and inflicts serious long-term damage and disability. The vasoconstrictor Endothelin-1, presenting long-term neurological deficits associated with excitotoxicity and oxidative stress is being increasingly used to induce focal ischemic injury as a model of stroke. A DJ-1 based peptide named ND-13 was shown to protect against glutamate toxicity, neurotoxic insults and oxidative stress in various animal models. Here we focus on the benefits of treatment with ND-13 on the functional outcome of focal ischemic injury. Wild type C57BL/6 mice treated with ND-13, after ischemic induction in this model, showed significant improvement in motor function, including improved body balance and motor coordination, and decreased motor asymmetry. We found that DJ-1 knockout mice are more sensitive to Endothelin-1 ischemic insult than wild type mice, contributing thereby additional evidence to the widely reported relevance of DJ-1 in neuroprotection. Furthermore, treatment of DJ-1 knockout mice with ND-13, following Endothelin-1 induced ischemia, resulted in significant improvement in motor functions, suggesting that ND-13 provides compensation for DJ-1 deficits. These preliminary results demonstrate a possible basis for clinical application of the ND-13 peptide to enhance neuroprotection in stroke patients.
Highlights
Stroke is the second most common cause of death, causing 9% of all deaths around the world, and is the most frequent cause of permanent disability in adults worldwide [1]
We found that treatment with ND-13 significantly improves the motor function of both wild type and DJ-1 knockout (DJ-1 KO) mice following induced focal ischemia
We have identified a decrease in the levels of Cereblon protein (CRBN) following ND-13 treatment (ND-13: 1.77E+07 ±3.55E+06; Vehicle: 1.19E+08 ±2.52E+07; fold change: 6.7, p
Summary
Stroke is the second most common cause of death, causing 9% of all deaths around the world, and is the most frequent cause of permanent disability in adults worldwide [1]. When the flow of blood to the brain is suddenly stopped, neuronal function is impaired and pathological pathways are triggered, causing irreversible neuronal damage in the ischemic area within minutes of onset. In the hours and days following stroke, the damaged regions undergo a broad scale necrosis, which causes the death of many types of cells [1,2,3]. Failure of energy production causes a flood of neurotransmitters to be released from neurons, mostly release of the excitatory glutamate, which further amplifies the damage [4,5].
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