KDI tripeptide of γ1 laminin protects rat dopaminergic neurons from 6‐OHDA induced toxicity

Abstract

Our previous studies indicate that the KDI (Lys-Asp-Ile) tripeptide of gamma1 laminin protects central neurons from mechanical trauma and excitotoxicity. At least part of the neuroprotective effect of the KDI tripeptide may be mediated by its inhibitory function on ionotropic glutamate receptors. We studied the protective effect of the KDI tripeptide against 6-hydroxy-dopamine (6-OHDA) induced neurotoxicity in a rat experimental model of Parkinson's disease (PD). We found that a single unilateral injection of the KDI tripeptide into the substantia nigra before an injection of 6-OHDA protected the dopaminergic neurons from the neurotoxicity of 6-OHDA. Compared to rats treated with 6-OHDA alone, the KDI + 6-OHDA-treated substantia nigra was relatively intact with large numbers of dopaminergic neurons present at the injection side. In the rats treated with 6-OHDA alone, no dopaminergic neurons were detected, and the substantia nigra-area at the injection side was filled with blood-containing cavities. Quantification of the rescue effect of the KDI tripeptide indicated that, in animals receiving KDI before 6-OHDA, 33% of tyrosine hydroxylase-positive dopaminergic neurons of the substantia nigra were present as compared to the contralateral non-injected side. In animals receiving 6-OHDA alone, only 1.4% of the tyrosine hydroxylase expressing dopaminergic neurons could be verified. If this much protection were achieved in humans, it would be sufficient to diminish or greatly alleviate the clinical symptoms of PD. We propose that the KDI tripeptide or its derivatives might offer a neuroprotective biological alternative for treatment of PD.

Laminins and their receptors in the CNS

“…Laminin-α2 expression has been reported in neuronal processes in the limbic system in both rats and rabbits (Hagg et al, 1997). Laminin-γ 1 is detected in hippocampal neurons (Grimpe et al, 2002) and dopaminergic neurons in substantia nigra and ventral tegemental area (Väänänen et al, 2006). In addition, laminin-511 expression has been reported in neurons from hippocampus and dentate gyrus at both mRNA and protein levels (Chen & Strickland, 1997;Indyk et al, 2003;Omar et al, 2017).…”

“…Third, there are studies showing that laminins also participate in the elimination of Aβ40 from brain parenchyma through perivascular drainage (Hawkes et al, 2012;Zekonyte et al, 2016). Furthermore, small peptides from laminin-α1 and the KDI tripeptide from laminin-γ 1 have been shown to reduce neurotoxicity (Liesi, 2009) and enhance dopaminergic neuron survival (Väänänen et al, 2006), respectively. These results suggest a neuroprotective role of laminins in neurodegeneration.…”

Proregenerative Properties of ECM Molecules

“…In addition, functional recovery has also been seen in spinal cord injury after injection of self-assembling nanofibres that present the laminin-derived IKVAV epitope at high density [81]. Injection of another laminin-derived peptide (KDI) protects dopaminergic neurons from 6-hydroxydopamine-induced injury [82] and improves regeneration and functional recovery after spinal cord injury in rats [83]. …”

Bivalent KDP Peptide to Enhance Neurite Growth for Traumatic Brain Injury

“…The decapeptide of γ1 laminin induces potassium currents in primary cultured cerebellar neurons. The smallest peptide is capable of inducing the same properties and supporting neurite outgrowth is the KDI tripeptide 14,15 .…”

“…The role of KDI tripeptide in promoting the survival of CNS neurons has been recently shown in Parkinson's disease 14 . The KDI tripeptide was the first compound to be used to protect the dopaminergic neurons of the rat substantia nigra (SN) against death induced by high doses 6-hydroxydopamine (OHDA) 14 to such an extent that over 30% of the dopaminergic neurons of the injected SN remained viable 14 . Bivalent approach has been applied to conjugate two KDP peptide molecule through glutamate linker which is finally conjugated to DO3A to yield the desired imaging agent. The proposed design is aimed to obtain a higher affinity of the molecule towards the target receptors 16 .…”