Scope of new formulation approaches in the repurposing of pioglitazone for the management of Alzheimer’s disease

Jojo, Gifty M; Kuppusamy, Gowthamarajan

doi:10.1111/jcpt.12808

Cited by 29 publications

(22 citation statements)

References 111 publications

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“…TZD derivatives, including rosiglitazone and pioglitazone, act as PPARγ agonists and are used for T2DM treatment because of their insulin sensitization activity [ 144 , 145 ]. They have also been researched as alternative AD treatments [ 146 , 147 ]. Increased adiponectin by TZD might play a key role in the insulin sensitization activity induced by TZD [ 132 , 148 ].…”

Section: Adiponectin-associated Therapeutic Strategy Against Ad Inmentioning

confidence: 99%

Adiponectin: The Potential Regulator and Therapeutic Target of Obesity and Alzheimer’s Disease

Kim

Barua

Jeong

et al. 2020

IJMS

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Animal and human mechanistic studies have consistently shown an association between obesity and Alzheimer’s disease (AD). AD, a degenerative brain disease, is the most common cause of dementia and is characterized by the presence of extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles disposition. Some studies have recently demonstrated that Aβ and tau cannot fully explain the pathophysiological development of AD and that metabolic disease factors, such as insulin, adiponectin, and antioxidants, are important for the sporadic onset of nongenetic AD. Obesity prevention and treatment can be an efficacious and safe approach to AD prevention. Adiponectin is a benign adipokine that sensitizes the insulin receptor signaling pathway and suppresses inflammation. It has been shown to be inversely correlated with adipose tissue dysfunction and may enhance the risk of AD because a range of neuroprotection adiponectin mechanisms is related to AD pathology alleviation. In this study, we summarize the recent progress that addresses the beneficial effects and potential mechanisms of adiponectin in AD. Furthermore, we review recent studies on the diverse medications of adiponectin that could possibly be related to AD treatment, with a focus on their association with adiponectin. A better understanding of the neuroprotection roles of adiponectin will help clarify the precise underlying mechanism of AD development and progression.

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Section: Adiponectin-associated Therapeutic Strategy Against Ad Inmentioning

confidence: 99%

Adiponectin: The Potential Regulator and Therapeutic Target of Obesity and Alzheimer’s Disease

Kim

Barua

Jeong

et al. 2020

IJMS

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“…Fifty-five hematological, blood coagulation, and serum biochemistry parameters monitored showed virtually no changes. As another issue, efficiencies of the synthetic PPARγ agonists for therapeutic use in patients with Alzheimer's may be limited somewhat by their nerve and brain permeability [47].…”

Section: Building a Better Therapeuticmentioning

confidence: 99%

Building and Testing PPARγ Therapeutic ELB00824 with an Improved Therapeutic Window for Neuropathic Pain

Westlund

Zhang²

2020

Molecules

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Effective, non-addictive therapeutics for chronic pain remain a critical need. While there are several potential therapeutics that stimulate anti-inflammatory mechanisms to restore homeostasis in the spinal dorsal horn microenvironment, the effectiveness of drugs for neuropathic pain are still inadequate. The convergence of increasing knowledge about the multi-factorial mechanisms underlying neuropathic pain and the mechanisms of drug action from preclinical studies are providing the ability to create pharmaceuticals with better clinical effectiveness. By targeting and activating the peroxisome proliferator-activated receptor gamma subunit (PPARγ), numerous preclinical studies report pleiotropic effects of thiazolidinediones (TDZ) beyond their intended use of increasing insulin, including their anti-inflammatory, renal, cardioprotective, and oncopreventative effects. Several studies find TDZs reduce pain-related behavioral symptoms, including ongoing secondary hypersensitivity driven by central sensitization. Previous studies find increased PPARγ in the spinal cord and brain regions innervated by incoming afferent nerve endings after the induction of neuropathic pain models. PPARγ agonist treatment provides an effective reduction in pain-related behaviors, including anxiety. Data further suggest that improved brain mitochondrial bioenergetics after PPARγ agonist treatment is a key mechanism for reducing hypersensitivity. This review emphasizes two points relevant for the development of better chronic pain therapies. First, employing neuropathic pain models with chronic duration is critical since they can encompass the continuum of molecular and brain circuitry alterations arising over time when pain persists, providing greater relevance to clinical pain syndromes. Assisting in that effort are preclinical models of chronic trigeminal pain syndromes. Secondly, considering the access to nerve and brain neurons and glia across the blood–brain barrier is important. While many therapies have low brain penetrance, a PPARγ agonist with better brain penetrance, ELB00824, has been developed. Purposeful design and recent comparative testing indicate that ELB00824 is extraordinarily efficient and efficacious. ELB00824 provides greatly improved attenuation of pain-related behaviors, including mechanical hypersensitivity, anxiety, and depression in our chronic trigeminal nerve injury models. Physiochemical properties allowing significant brain access and toxicity testing are discussed.

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“…12 Subsequently, rosiglitazone and pioglitazone were investigated through phase III clinical trials for AD, but failed. 13 One likely explanation for the failure of the aforementioned clinical trials is the poor transport of these drugs across the blood-brain-barrier (BBB), thus limiting the amount of drug that reached the brain of patients enrolled in these clinical trials. 14 Indeed, it is estimated that the BBB prevents about 98% of all small molecule drugs from reaching the brain, and only a fraction of the drug that enters the brain reaches the microglia.…”

Section: Introductionmentioning

confidence: 99%

Dendrimer–tesaglitazar conjugate induces a phenotype shift of microglia and enhances β-amyloid phagocytosis

et al. 2021

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Scope of new formulation approaches in the repurposing of pioglitazone for the management of Alzheimer’s disease

Cited by 29 publications

References 111 publications

Adiponectin: The Potential Regulator and Therapeutic Target of Obesity and Alzheimer’s Disease

Adiponectin: The Potential Regulator and Therapeutic Target of Obesity and Alzheimer’s Disease

Building and Testing PPARγ Therapeutic ELB00824 with an Improved Therapeutic Window for Neuropathic Pain

Dendrimer–tesaglitazar conjugate induces a phenotype shift of microglia and enhances β-amyloid phagocytosis

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