A novel protective modality against rotenone-induced Parkinson's disease: A pre-clinical study with dulaglutide

Khalaf, Marwa M.; Elsayed, Mahmoud M. A.; Kandeil, Mohamed A.; Ahmed, Soliman

doi:10.1016/j.intimp.2023.110170

Cited by 3 publications

(1 citation statement)

References 67 publications

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“…As mentioned above, Exenatide provided reliable evidence of improving motor and non-motor symptoms in PD, but its role in reducing the pathophysiology and background brain injury in humans currently needs to be clarified [294]. Promising results have also been elucidated by a preclinical study with Dulaglutide, in which GLP-1RAs were demonstrated to reduce neuroinflammation and promote neurodegeneration [295]. However, more investigation is essential to clarify several issues, including the potential for preventing the onset of degenerative diseases, including PD, in predisposing clinical conditions, such as T2D, efficacy and safety, and durability of treatment in the early and late-stage disease.…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

Dopamine in the Regulation of Glucose Homeostasis, Pathogenesis of Type 2 Diabetes, and Chronic Conditions of Impaired Dopamine Activity/Metabolism: Implication for Pathophysiological and Therapeutic Purposes

Lisco,

De Tullio,

Iovino

et al. 2023

Biomedicines

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Dopamine regulates several functions, such as voluntary movements, spatial memory, motivation, sleep, arousal, feeding, immune function, maternal behaviors, and lactation. Less clear is the role of dopamine in the pathophysiology of type 2 diabetes mellitus (T2D) and chronic complications and conditions frequently associated with it. This review summarizes recent evidence on the role of dopamine in regulating insular metabolism and activity, the pathophysiology of traditional chronic complications associated with T2D, the pathophysiological interconnection between T2D and chronic neurological and psychiatric disorders characterized by impaired dopamine activity/metabolism, and therapeutic implications. Reinforcing dopamine signaling is therapeutic in T2D, especially in patients with dopamine-related disorders, such as Parkinson’s and Huntington’s diseases, addictions, and attention-deficit/hyperactivity disorder. On the other hand, although specific trials are probably needed, certain medications approved for T2D (e.g., metformin, pioglitazone, incretin-based therapy, and gliflozins) may have a therapeutic role in such dopamine-related disorders due to anti-inflammatory and anti-oxidative effects, improvement in insulin signaling, neuroinflammation, mitochondrial dysfunction, autophagy, and apoptosis, restoration of striatal dopamine synthesis, and modulation of dopamine signaling associated with reward and hedonic eating. Last, targeting dopamine metabolism could have the potential for diagnostic and therapeutic purposes in chronic diabetes-related complications, such as diabetic retinopathy.

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Section: Therapeutic Implicationsmentioning

confidence: 99%

Dopamine in the Regulation of Glucose Homeostasis, Pathogenesis of Type 2 Diabetes, and Chronic Conditions of Impaired Dopamine Activity/Metabolism: Implication for Pathophysiological and Therapeutic Purposes

Lisco,

De Tullio,

Iovino

et al. 2023

Biomedicines

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Single-neuron neurodegeneration as a degenerative model for Parkinson’s disease

Huenchuguala

Segura‐Aguilar

2023

Neural Regeneration Research

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The positive effect of levodopa in the treatment of Parkinson’s disease, although it is limited in time and has severe side effects, has encouraged the scientific community to look for new drugs that can stop the neurodegenerative process or even regenerate the neuromelanin-containing dopaminergic nigrostriatal neurons. Successful preclinical studies with coenzyme Q10, mitoquinone, isradipine, nilotinib, TCH346, neurturin, zonisamide, deferiprone, prasinezumab, and cinpanemab prompted clinical trials. However, these failed and after more than 50 years levodopa continues to be the key drug in the treatment of the disease, despite its severe side effects after 4–6 years of chronic treatment. The lack of translated successful results obtained in preclinical investigations based on the use of neurotoxins that do not exist in the human body as new drugs for Parkinson’s disease treatment is a big problem. In our opinion, the cause of these failures lies in the experimental animal models involving neurotoxins that do not exist in the human body, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine, that induce a very fast, massive and expansive neurodegenerative process, which contrasts with the extremely slow one of neuromelanin-containing dopaminergic neurons. The exceedingly slow progress of the neurodegenerative process of the nigrostriatal neurons in idiopathic Parkinson’s patients is due to (i) a degenerative model in which the neurotoxic effect of an endogenous neurotoxin affects a single neuron, (ii) a neurotoxic event that is not expansive and (iii) the fact that the neurotoxin that triggers the neurodegenerative process is produced inside the neuromelanin-containing dopaminergic neurons. The endogenous neurotoxin that fits this degenerative model involving one single neuron at a time is aminochrome, since it (i) is generated within neuromelanin-containing dopaminergic neurons, (ii) does not cause an expansive neurotoxic effect and (iii) triggers all the mechanisms involved in the neurodegenerative process of the nigrostriatal neurons in idiopathic Parkinson’s disease. In conclusion, based on the hypothesis that the neurodegenerative process of idiopathic Parkinson’s disease corresponds to a single-neuron neurodegeneration model, we must search for molecules that increase the expression of the neuroprotective enzymes DT-diaphorase and glutathione transferase M2-2. It has been observed that the activation of the Kelch-like ECH-associated protein 1/nuclear factor (erythroid-derived 2)-like 2 pathway is associated with the transcriptional activation of the DT-diaphorase and glutathione transferase genes.

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Neuroprotective Activity of GLP-1 Analogues: General Understanding of Implementation Mechanisms

Golovina,

Vaizova,

Samojlova

2024

jour

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Glucagon-like peptide-1 (GLP-1) is a hormone possessing extensive pharmacologic potential. Additionally, to its multiple metabolic effects, GLP-1 also exhibits cardiac and neuroprotective effects. Native GLP-1 is not used as a medicinal agent, however, now GLP-1 analogues structurally similar to it and having a long-lasting effect have been developed and used in the treatment of type 2 diabetes mellitus (T2DM). The review focuses on the neuroprotective effect of these drugs and discusses possible mechanisms of this effect. Aim: To identify information about experimental and clinical evidence about the role of GLP-1 analogues in brain protection in neurodegenerative dis[1]eases. Materials and Methods: The review was performed in accordance with the PRISMA 2020 statement; publications were searched for in the PubMed, MedLine, Web of Science, Scopus, and Google Scholar databases covering the period from 2014 to 2024. Results: The publications provide strong evidence of the association between T2DM and cognitive impairment, as well as information on the effectiveness of GLP-1 analogues in the management of neurodegenerative diseases. Possible mechanisms are discussed. Conclusion: This review shows that GLP-1 can prevent cognitive and motor disorders. There is sufficient experimental evidence of the neurotropic activity of the drugs, and clinical trials are ongoing.

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A novel protective modality against rotenone-induced Parkinson's disease: A pre-clinical study with dulaglutide

Cited by 3 publications

References 67 publications

Dopamine in the Regulation of Glucose Homeostasis, Pathogenesis of Type 2 Diabetes, and Chronic Conditions of Impaired Dopamine Activity/Metabolism: Implication for Pathophysiological and Therapeutic Purposes

Dopamine in the Regulation of Glucose Homeostasis, Pathogenesis of Type 2 Diabetes, and Chronic Conditions of Impaired Dopamine Activity/Metabolism: Implication for Pathophysiological and Therapeutic Purposes

Single-neuron neurodegeneration as a degenerative model for Parkinson’s disease

Neuroprotective Activity of GLP-1 Analogues: General Understanding of Implementation Mechanisms

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