Dipeptide Analog of Neurotensin Active Site Prevents the Development of Experimental Parkinson's Syndrome in Mice

Abstract

Chronic administration of neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (30 mg/kg) to C57BL/6 mice caused death of all animals within 7 days. Dipeptide analog of neurotensin active site injected with this neurotoxin protected the mice from death even after 2-week intoxication. When younger mice and lower dose of neurotoxin (25 mg/kg) were used, all animals survived, but after 2 weeks they developed parkinsonian syndrome with muscular rigidity, akinesia, decrease in motor and explorative activities. In mice treated with dipeptide analog of neurotensin active site these manifestations of oligokinesia caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine were less pronounced and the corresponding parameters approximated the control values. Possible mechanisms of neuroprotective action of neurotensin active site analog are discussed.

Striatal NTS1, dopamine D2 and NMDA receptor regulation of pallidal GABA and glutamate release – a dual‐probe microdialysis study in the intranigral 6‐hydroxydopamine unilaterally lesioned rat

“…An antiparkinsonian‐like profile for certain NT receptor analogues (Boules et al. , 2001, 2006; Lutsenko et al. , 2003; Xue et al.…”

“…The use of selective NTS 1 antagonists in combination with conventional drug treatments may provide a novel therapeutic approach for the treatment of Parkinson's disease based inter alia on the neurochemical and behavioural evidence obtained in the current paper in a rat model of Parkinson's disease. An antiparkinsonian-like profile for certain NT receptor analogues (Boules et al, 2001(Boules et al, , 2006Lutsenko et al, 2003;Xue et al, 2009) may be related to partial antagonist and ⁄ or inverse agonist actions at NTS 1 receptors. Our findings emphasize the importance of further preclinical investigations to understand the molecular basis of the ability of the NTS 1 receptor antagonists to reduce the drive of the striatopallidal GABA neurons and to define the antiparkinsonian-like properties of NTS 1 receptor antagonists.…”

Neurotensin-Binding Immunoglobulin G in Patients with Parkinson’s Disease

“…NTS is produced in the brain but also in the enteroendocrine cells of the gut [29,30]. Peripheral administration of NTS analogs in a rat model of PD reduced the symptoms severity, while in vitro studies show its potent neuroprotective effect [9,10,31]. Whether peripheral NTS bound to IgG may reach the brain and protect DA neurons is presently unknown.…”

“…Importantly, NTS along with several other neuropeptides display neuroprotective effects for the DA system and PD [8]. Indeed, experimental studies in rodents showed that NTS analogs may protect against PD-like symptomatology [9,10]. Moreover, NTSR can be used for the targeted delivery of neuroprotective factors' genes into the SN DA neurons [11].…”

Parkinson’s disease, epilepsy, and amyotrophic lateral sclerosis—emerging role of AMPA and kainate subtypes of ionotropic glutamate receptors

“…Although glutamatergic signaling increases and stimulates the release of dopamine through surviving dopaminergic neurons in the SNpc as a compensatory mechanism, increasing glutamate concentrations and excessive activation of glutamate receptors could be a “critical strike” to dopaminergic neurons in PD patients as well ( Wang et al, 2020 ). The approved PD treatments include the use of dopamine receptor agonists (for example, L-DOPA), dopamimetic drugs to relieve the symptoms of impaired motor function ( Lutsenko et al, 2003 ), and deep brain stimulation techniques ( Malek, 2019 ). Although these forms of treatment may partially ameliorate the motor dysfunctions of PD patients, they do not slow the disease progression.…”