Drotaverine Inhibitor of PDE4: Reverses the Streptozotocin Induced Alzheimer’s Disease in Mice

Nazir, Samra; Anwar, Fareeha; Saleem, Uzma; Ahmad, Bashir; Raza, Zohaib; Sanawar, Maham; Rehman, Artta Ur; Ismail, Tariq

doi:10.1007/s11064-021-03327-9

Cited by 10 publications

(22 citation statements)

References 41 publications

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“…where OD is the change in absorbance, and E is the extinction coefficient of H 2 O 2 (0.071 mmol/cm). Total protein was estimated using the Lowery method ( Nazir et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Acute Oral, Subacute, and Developmental Toxicity Profiling of Naphthalene 2-Yl, 2-Chloro, 5-Nitrobenzoate: Assessment Based on Stress Response, Toxicity, and Adverse Outcome Pathways

et al. 2022

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The U.S. National Research Council (NRC) introduced new approaches to report toxicity studies. The NRC vision is to explore the toxicity pathways leading to the adverse effects in intact organisms by the exposure of the chemicals. This study examines the toxicity profiling of the naphthalene-2-yl 2-chloro-5-dinitrobenzoate (SF5) by adopting the vision of NRC that moves from traditional animal studies to the cellular pathways. Acute, subacute, and developmental toxicity studies were assayed according to the Organization for Economic Cooperation and Development (OECD) guidelines. The stress response pathway, toxicity pathway, and adverse effects outcome parameters were analyzed by using their standard protocols. The results showed that the acute toxicity study increases the liver enzyme levels. In a subacute toxicity study, alkaline phosphatase (ALP) levels were raised in both male and female animals. SF5 significantly increases the normal sperm count in the male animals corresponding to a decrease in the abnormality count. Developmental toxicity showed the normal skeletal and morphological parameters, except little hydrocephalus was observed in developmental toxicity. Doses of 20 mg/kg in males and 4 mg/kg in females showed decreased glutathione (GSH) levels in the kidney and liver. MDA levels were also increased in the kidney and liver. However, histopathological studies did not show any cellular change in these organs. No statistical difference was observed in histamine levels, testosterone, nuclear factor erythroid two-related factor-2 (Nrf2), and nuclear factor-kappa B (NF-κB), which showed no initiation of the stress response, toxicity, and adverse effect pathways. Immunomodulation was observed at low doses in subacute toxicity studies. It was concluded that SF5 did not produce abrupt and high-toxicity levels in organs and biochemical parameters. So, it is safe for further studies.

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“…where OD is the change in absorbance, and E is the extinction coefficient of H 2 O 2 (0.071 mmol/cm). Total protein was estimated using the Lowery method ( Nazir et al, 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Acute Oral, Subacute, and Developmental Toxicity Profiling of Naphthalene 2-Yl, 2-Chloro, 5-Nitrobenzoate: Assessment Based on Stress Response, Toxicity, and Adverse Outcome Pathways

et al. 2022

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“…Superoxide dismutase quickly reduced the oxygen to superoxide anionic radicals. 39 The resultant mixture absorbance was recorded at 325 nm using a UV spectrophotometer. The superoxide dismutase level was estimated through the slope equation Y = 0.0095 X + 0.1939.…”

Section: Experimental Animalsmentioning

confidence: 99%

“…The sample was permitted to cool down, and the absorbance was estimated at 350 and 450 nm for dopamine and noradrenaline, respectively. 39 To perform the reverse-order oxidation, the blank was synthesized by adding reagents, i.e., sodium sulfate before iodine solution. Final calculations were carried out using the following regression line equations: for dopamine, Y = 0.2331 X + 0.0164, and for noradrenaline, Y = 0.1008 X + 0.2508.…”

Section: Experimental Animalsmentioning

confidence: 99%

“…A color change was noticed at 450 nm. 39 Protein levels were estimated by the standard curve. 1–40 Aβ amyloid levels (pg/mL) were observed through the following mentioned regression line Y = 0.00397 X + 0.1504, and the tau protein levels were estimated using Y = 0.0008508 X + 0.7008.…”

Section: Protein Analysis By Elisamentioning

confidence: 99%

“…This pyrogallol is one of the known oxidizing agents that were used to work under alkaline conditions with generation of oxygen. Superoxide dismutase quickly reduced the oxygen to superoxide anionic radicals . The resultant mixture absorbance was recorded at 325 nm using a UV spectrophotometer.…”

Section: Experimental Animalsmentioning

confidence: 99%

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Prospective Evaluation of an Amide-Based Zinc Scaffold as an Anti-Alzheimer Agent: In Vitro, In Vivo, and Computational Studies

et al. 2022

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Alzheimer’s disease is the most common progressive neurodegenerative mental disorder associated with loss of memory, decline in cognitive function, and dysfunction of language. The prominent pathogenic causes of this disease involve deposition of amyloid-β plaques, acetylcholine neurotransmitter deficiency, and accumulation of neurofibrillary tangles. There are multiple pathways that have been targeted to treat this disease. The inhibition of the intracellular cyclic AMP regulator phosphodiesterase IV causes the increase in CAMP levels that play an important role in the memory formation process. Organometallic chemistry works in a different way in treating pharmacological disorders. In the field of medicinal chemistry and pharmaceuticals, zinc-based amide carboxylates have been shown to be a preferred pharmacophore. The purpose of this research work was to investigate the potential of zinc amide carboxylates in inhibition of phosphodiesterase IV for the Alzheimer’s disease management. Swiss Albino mice under controlled conditions were divided into seven groups with 10 mice each. Group I was injected with carboxymethylcellulose (CMC) at 1 mL/100 g dose, group II was injected with Streptozotocin (STZ) at 3 mg/kg dose, group III was injected with Piracetam acting as a standard drug at 200 mg/kg dosage, while groups IV–VII were injected with a zinc scaffold at the dose regimen of 10, 20, 40, and 80 mg/kg through intraperitoneal injection. All groups except group I were injected with Streptozotocin on the first day and third day of treatment at the dose of 3 mg/kg through an intracerebroventricular route to induce Alzheimer’s disease. Afterward, respective treatment was continued for all groups for 23 days. In between the treatment regimen, groups were analyzed for memory and learning improvement through various behavioral tests such as open field, elevated plus maze, Morris water maze, and passive avoidance tests. At the end of the study, different biochemical markers in the brain were estimated like neurotransmitters (dopamine, serotonin and adrenaline), oxidative stress markers (superoxide dismutase, glutathione, and catalase), acetylcholinesterase (AchE), tau proteins, and amyloid-β levels. A PCR study was also performed. Results showed that the LD 50 of the zinc scaffold is greater than 2000 mg/kg. Research indicated that the zinc scaffold has the potential to improve the memory impairment and learning behavior in Alzheimer’s disease animal models in a dose-dependent manner. At the dose of 80 mg/kg, a maximum response was observed for the zinc scaffold. Maximum reduction in the acetylcholinesterase enzyme was observed at 80 mg/kg dose, which was further strengthened and verified by the PCR study. Oxidative stress was restored by the zinc scaffold due to the significant activation of the endogenous antioxidant enzymes. This research ended up with the conclusion that the zinc-based amide carboxylate scaffold has the potential to improve behavioral disturbances and vary the biochemica...

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Selective inhibition of phosphodiesterase 4D increases tau phosphorylation at Ser214 residue

et al. 2022

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Tau is a protein that normally participates in the assembly and stability of microtubules. However, it can form intraneuronal hyperphosphorylated aggregates that are hallmarks of Alzheimer's disease and other neurodegenerative disorders known as tauopathies. Tau can be phosphorylated by multiple kinases at several sites. Among such kinases, the cAMP‐dependent protein kinase A (PKA) phosphorylates tau at Ser214 (pTAU‐S214), an event that was shown to reduce the pathological assembly of the protein. Given that the neuronal cAMP/PKA‐activated cascade is involved in synaptic plasticity and memory, and that cAMP‐enhancing strategies demonstrated promising therapeutic potential for the treatment of cognitive deficits, we investigated the impact of cAMP on pTAU‐S214 in N2a cells and rat hippocampal slices. Our results confirm that the activation of adenylyl cyclase increases pTAU‐S214 in both model systems and, more interestingly, this effect is mimicked by GEBR‐7b, a phosphodiesterase 4D inhibitor with proven pro‐cognitive efficacy in rodents.

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Drotaverine Inhibitor of PDE4: Reverses the Streptozotocin Induced Alzheimer’s Disease in Mice

Cited by 10 publications

References 41 publications

Acute Oral, Subacute, and Developmental Toxicity Profiling of Naphthalene 2-Yl, 2-Chloro, 5-Nitrobenzoate: Assessment Based on Stress Response, Toxicity, and Adverse Outcome Pathways

Acute Oral, Subacute, and Developmental Toxicity Profiling of Naphthalene 2-Yl, 2-Chloro, 5-Nitrobenzoate: Assessment Based on Stress Response, Toxicity, and Adverse Outcome Pathways

Prospective Evaluation of an Amide-Based Zinc Scaffold as an Anti-Alzheimer Agent: In Vitro, In Vivo, and Computational Studies

Selective inhibition of phosphodiesterase 4D increases tau phosphorylation at Ser214 residue

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