Therapeutic potential of α7 nicotinic receptor agonists to regulate neuroinflammation in neurodegenerative diseases

Neurodegenerative diseases, such as Alzheimer's, Parkinson's and Huntington's diseases, are all characterized by a component of innate immunity called neuroinflammation. Neuronal loss and neuroinflammation are two phenomena closely linked. Hence, the neuroinflammation is a relevant target for the management of the neurodegenerative diseases given that, to date, there is no treatment to stop neuronal loss. Several studies have investigated the potential effects of activators of alpha 7 nicotinic acetylcholine receptors in animal models of neurodegenerative diseases. These receptors are widely distributed in the central nervous system. After activation, they seem to mediate the cholinergic anti-inflammatory pathway in the brain. This anti-inflammatory pathway, first described in periphery, regulates activation of microglial cells considered as the resident macrophage population of the central nervous system. In this article, we shortly review the agonists of the alpha 7 nicotinic acetylcholine receptors that have been evaluated in vivo and we focused on the selective positive allosteric modulators of these receptors. These compounds represent a key element to enhance receptor activity only in the presence of the endogenous agonist

Dénominations et indications des anticorps face à la réglementation et aux pratiques des laboratoires pharmaceutiques

Les dénominations et les indications des anticorps monoclonaux thérapeutiques doivent répondre aux réglementations en vigueur, mais s’accompagnent du développement de stratégies commerciales autour des noms commerciaux. Certaines de ces pratiques obéissent à des considérations territoriales ou juridiques, tandis que d’autres sont motivées par de réelles préoccupations médicales. Enfin, certaines ont un impact financier non négligeable pour la collectivité

Alpha-7 nicotinic acetylcholine receptor agonist treatment in a rat model of Huntington's disease and involvement of heme oxygenase-1

Neuroinflammation is a common element involved in the pathophysiology of neurodegenerative diseases. We recently reported that repeated alpha-7 nicotinic acetylcholine receptor (α7nAChR) activations by a potent agonist such as PHA 543613 in quinolinic acid-injured rats exhibited protective effects on neurons. To further investigate the underlying mechanism, we established rat models of early-stage Huntington's disease by injection of quinolinic acid into the right striatum and then intraperitoneally injected 12 mg/kg PHA 543613 or sterile water, twice a day during 4 days. Western blot assay results showed that the expression of heme oxygenase-1 (HO-1), the key component of the cholinergic anti-inflammatory pathway, in the right striatum of rat models of Huntington's disease subjected to intraperitoneal injection of PHA 543613 for 4 days was significantly increased compared to the control rats receiving intraperitoneal injection of sterile water, and that the increase in HO-1 expression was independent of change in α7nAChR expression. These findings suggest that HO-1 expression is unrelated to α7nAChR density and the increase in HO-1 expression likely contributes to α7nAChR activation-related neuroprotective effect in early-stage Huntington's disease

Why is there no biosimilar of Erbitux®?

Monoclonal antibody (mAb)-based therapies have been a major advance in oncology patient care, even though they represent a significant healthcare cost. Biosimilars, launched in Europe in 2004 are an economically attractive alternative to expensive originator biological drugs. They also increase the competitiveness of pharmaceutical development. This article focuses on the case of Erbitux® (cetuximab). This anti-EGFR (Epidermal Growth Factor Receptor) monoclonal antibody is indicated for metastatic colorectal cancer (2004) and squamous cell carcinoma of the head and neck (2006). However, despite the expiration of the patent in Europe in 2014 and estimated annual sales of 1.681 million US dollars in 2022, Erbitux® has not yet faced any approved biosimilar challenges in the United States or in Europe. Here, we outline the unique structural complexity of this antibody highlighted by advanced orthogonal analytical characterization strategies resulting in risks to demonstrate biosimilarity, which may explain the lack of Erbitux® biosimilars in the European and US markets to date. The development of Erbitux® biobetters are also discussed as alternative strategies to biosimilars. These biologics offer expected additional safety and potency benefits over the reference product but require a full pharmaceutical and clinical development as for New Molecular Entities

Neuroprotective and anti-inflammatory effects of a therapy combining agonists of nicotinic α7 and σ1 receptors in a rat model of Parkinson's disease

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An automated alert system based on the p-Tau/Tau ratio to quickly inform health professionals upon a suspected case of sporadic Creutzfeldt-Jakob disease.

International audienceIntroduction: Knowing the risk of potential sporadic Creutzfeldt-Jakob disease (sCJD) instrument-contamination is essential in hospitals. We examined the relevance of the p-Tau/Tau ratio to exclude a probable case of sCJD in clinical practice, and we established an alert system to quickly inform health professionals in case of positivity.Methods: This retrospective study was conducted on 143 cerebrospinal fluid samples from patients suspected for sCJD. The distinction between probable cases of sCJD and other patients was based on clinical, paraclinical and biological (14-3-3, Tau, p-Tau, Aβ 1-42) data. From this experience, the health professionals developed an alert system to be implemented upon a suspected case of sCJD.Results: A significant decrease in p-Tau/Tau ratio between sCJD and the other diseases was observed (p < 0 .001). The combined Tau test presented a sensitivity higher than 14-3-3 (100% versus 92.3%, p =0 .006) and an equivalent specificity (90% versus 96.1%). The time required for obtaining results was higher for 14-3-3 due to the centralization of investigations in some laboratories (3 weeks versus 2 h). In the presence of these elements, the triggering of the alert system was based on the p-Tau/Tau ratio. This system involves sending an automatic mail to the hospital department involved in the patient's care and the hospital hygiene team, which oversees the application of the procedures.Conclusion: The p-Tau/Tau concentrations present the desired criteria for use in current medical practice to fight against iatrogenic transmission. The alert system confirms a probable case of sCJD instantly to health professionals. Hygiene and sterilization measures can be applied immediately

Neuroprotective effect of the alpha 7 nicotinic receptor agonist PHA 543613 in an in vivo excitotoxic adult rat model

International audienceNeuroinflammation is a key component of the pathophysiology of neurodegenerative diseases. The link between nicotine intake and positive outcome has been established, suggesting a role played by nicotinic receptors (nAChRs), especially α7nAChRs. The objective of this study was to evaluate the potential dose effects of PHA 543613 on neuron survival and striatal microglial activation in a rat model of brain excitotoxicity. A preliminary study was performed in vitro to confirm PHA 543613 agonist properties on α7nAChRs. Rats were lesioned in the right striatum with quinolinic acid (QA) and received either vehicle or PHA 543613 at 6 or 12 mg/kg twice a day until sacrifice at Day 4 post-lesion. We first compared the translocator protein quantitative autoradiography in QA-lesioned brains with [3H]DPA-714 and [3H]PK-11195. The effects of PHA 543613 on microglial activation and neuronal survival were then evaluated through [3H]DPA-714 binding and immunofluorescence staining (Ox-42, NeuN) on adjacent brain sections. We demonstrated that [3H]DPA-714 provides a better signal-to-noise ratio than [3H]PK-11195. Furthermore, we showed that repeated PHA 543613 administration at a dose of 12 mg/kg to QA-lesioned rats significantly protected neurons and reduced the intensity of microglial activation. This study reinforces the hypothesis that α7nAChR agonists can provide beneficial effects in the treatment of neurodegenerative diseases through potential modulation of microglial activation