Neuroprotective and Disease-Modifying Effects of the Triazinetrione ACD856, a Positive Allosteric Modulator of Trk-Receptors for the Treatment of Cognitive Dysfunction in Alzheimer’s Disease

Fernández, Carmen; Juric, Sanja; Backlund, Maria; Dahlström, Märta; Madjid, Nather; Lidell, Veronica; Rasti, Azita; Sandin, Johan; Nordvall, Gunnar; Forsell, Pontus

doi:10.3390/ijms241311159

Cited by 3 publications

(1 citation statement)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A positive allosteric modulator or Trk receptor, ACD856, increased the levels of BDNF in aged mice, adding to the results obtained in vitro demonstrating enhanced nerve growth factor activity and neurite outgrowth and increased levels of the synaptic protein SNAP25 [ 153 ].…”

Section: Interventions Targeting Neuroplasticity In Animal Models Of Admentioning

confidence: 94%

Therapeutic Strategies Aimed at Improving Neuroplasticity in Alzheimer Disease

Colavitta,

Barrantes

2023

Pharmaceutics

View full text Add to dashboard Cite

Alzheimer disease (AD) is the most prevalent form of dementia among elderly people. Owing to its varied and multicausal etiopathology, intervention strategies have been highly diverse. Despite ongoing advances in the field, efficient therapies to mitigate AD symptoms or delay their progression are still of limited scope. Neuroplasticity, in broad terms the ability of the brain to modify its structure in response to external stimulation or damage, has received growing attention as a possible therapeutic target, since the disruption of plastic mechanisms in the brain appear to correlate with various forms of cognitive impairment present in AD patients. Several pre-clinical and clinical studies have attempted to enhance neuroplasticity via different mechanisms, for example, regulating glucose or lipid metabolism, targeting the activity of neurotransmitter systems, or addressing neuroinflammation. In this review, we first describe several structural and functional aspects of neuroplasticity. We then focus on the current status of pharmacological approaches to AD stemming from clinical trials targeting neuroplastic mechanisms in AD patients. This is followed by an analysis of analogous pharmacological interventions in animal models, according to their mechanisms of action.

show abstract

Section: Interventions Targeting Neuroplasticity In Animal Models Of Admentioning

confidence: 94%

Therapeutic Strategies Aimed at Improving Neuroplasticity in Alzheimer Disease

Colavitta,

Barrantes

2023

Pharmaceutics

View full text Add to dashboard Cite

show abstract

Targeting brain‐derived neurotrophic factor in the treatment of neurodegenerative diseases: A review

Wang,

Lang,

Wei

et al. 2024

Neuroprotection

View full text Add to dashboard Cite

Neurodegenerative diseases, marked by the gradual death of neurons, present a significant and growing public health challenge. Brain‐derived neurotrophic factor (BDNF) is crucial for the survival, development, and synaptic plasticity of neurons. Studies have consistently demonstrated that perturbed BDNF communication pathways are associated with the development and progression of neurodegenerative conditions, underscoring their potential as therapeutic targets. This review aimed to summarize the existing findings regarding BDNF expression, metabolism, and signaling transduction. Furthermore, we reviewed the intricate roles of BDNF signaling pathways in neurodegenerative diseases, elucidating their contributions to disease onset and progression. The latest advancements in targeting BDNF for the treatment of neurodegenerative diseases, including the development of small molecules, nucleic acid‐based therapeutics, and antibody‐based approaches, were also summarized. Despite recent strides, challenges persist, including a lack of comprehensive understanding of BDNF modulation across diverse neurodegenerative contexts and the absence of clinically approved BDNF‐targeted drugs.

show abstract

Positive Allosteric Modulators of Trk Receptors for the Treatment of Alzheimer’s Disease

Forsell,

Parrado Fernández,

Nilsson

et al. 2024

Pharmaceuticals

View full text Add to dashboard Cite

Neurotrophins are important regulators of neuronal and non-neuronal functions. As such, the neurotrophins and their receptors, the tropomyosin receptor kinase (Trk) family of receptor tyrosine kinases, has attracted intense research interest and their role in multiple diseases including Alzheimer’s disease has been described. Attempts to administer neurotrophins to patients have been reported, but the clinical trials have so far have been hampered by side effects or a lack of clear efficacy. Thus, much of the focus during recent years has been on identifying small molecules acting as agonists or positive allosteric modulators (PAMs) of Trk receptors. Two examples of successful discovery and development of PAMs are the TrkA-PAM E2511 and the pan-Trk PAM ACD856. E2511 has been reported to have disease-modifying effects in preclinical models, whereas ACD856 demonstrates both a symptomatic and a disease-modifying effect in preclinical models. Both molecules have reached the stage of clinical development and were reported to be safe and well tolerated in clinical phase 1 studies, albeit with different pharmacokinetic profiles. These two emerging small molecules are interesting examples of possible novel symptomatic and disease-modifying treatments that could complement the existing anti-amyloid monoclonal antibodies for the treatment of Alzheimer’s disease. This review aims to present the concept of positive allosteric modulators of the Trk receptors as a novel future treatment option for Alzheimer’s disease and other neurodegenerative and cognitive disorders, and the current preclinical and clinical data supporting this new concept. Preclinical data indicate dual mechanisms, not only as cognitive enhancers, but also a tentative neurorestorative function.

show abstract

Neuroprotective and Disease-Modifying Effects of the Triazinetrione ACD856, a Positive Allosteric Modulator of Trk-Receptors for the Treatment of Cognitive Dysfunction in Alzheimer’s Disease

Cited by 3 publications

References 78 publications

Therapeutic Strategies Aimed at Improving Neuroplasticity in Alzheimer Disease

Therapeutic Strategies Aimed at Improving Neuroplasticity in Alzheimer Disease

Targeting brain‐derived neurotrophic factor in the treatment of neurodegenerative diseases: A review

Positive Allosteric Modulators of Trk Receptors for the Treatment of Alzheimer’s Disease

Contact Info

Product

Resources

About