Melatonin Rescues the Dendrite Collapse Induced by the Pro-Oxidant Toxin Okadaic Acid in Organotypic Cultures of Rat Hilar Hippocampus

Abstract

The pro-oxidant compound okadaic acid (OKA) mimics alterations found in Alzheimer’s disease (AD) as oxidative stress and tau hyperphosphorylation, leading to neurodegeneration and cognitive decline. Although loss of dendrite complexity occurs in AD, the study of this post-synaptic domain in chemical-induced models remains unexplored. Moreover, there is a growing expectation for therapeutic adjuvants to counteract these brain dysfunctions. Melatonin, a free-radical scavenger, inhibits tau hyperphosphorylation, modulates phosphatases, and strengthens dendritic arbors. Thus, we determined if OKA alters the dendritic arbors of hilar hippocampal neurons and whether melatonin prevents, counteracts, or reverses these damages. Rat organotypic cultures were incubated with vehicle, OKA, melatonin, and combined treatments with melatonin either before, simultaneously, or after OKA. DNA breaks were assessed by TUNEL assay and nuclei were counterstained with DAPI. Additionally, MAP2 was immunostained to assess the dendritic arbor properties by the Sholl method. In hippocampal hilus, OKA increased DNA fragmentation and reduced the number of MAP2(+) cells, whereas melatonin protected against oxidation and apoptosis. Additionally, OKA decreased the dendritic arbor complexity and melatonin not only counteracted, but also prevented and reversed the dendritic arbor retraction, highlighting its role in post-synaptic domain integrity preservation against neurodegenerative events in hippocampal neurons.

Oxidative stress, the blood–brain barrier and neurodegenerative diseases: The critical beneficial role of dietary antioxidants

“…In the future, extensive research and human clinical trials are still required to realize the therapeutic potential of these medicinal products. Other preclinical and clinical studies of dietary antioxidant suplements with beneficial effects on NDs are described in Table 3 136 , 142 , 154 , 294 , 295 , 296 , 297 , 298 , 299 , 300 , 301 , 302 , 303 , 304 , 305 , 306 , 307 , 308 , 309 , 310 , 311 , 312 , 313 , 314 , 315 , 316 , 317 , 318 , 319 , 320 , 321 , 322 , 323 , 324 , 325 , 326 , 327 , 328 , 329 , 330 and Table 4 331 , 332 , 333 , 334 , 335 , 336 , 337 , 338 , 339 , 340 , 341 , 342 , 343 , 344 , 345 , 346 , 347 , 348 , 349 , 350 , 351 , …”

The Role of Dietary Antioxidants and Their Potential Mechanisms in Alzheimer’s Disease Treatment

“…Although Wade et al [ 47 ] did not examine melatonin’s impact on oxidative stress and inflammation biomarkers, several preclinical studies provided evidence that melatonin can reduce inflammation and oxidative stress related to AD. For example, melatonin ameliorated DNA fragmentation and apoptosis in rat hippocampal tissue cultures treated with okadaic acid, a pro-oxidant compound that can generate NFT in rat models [ 99 ]. In PC12 cells, agomelatine—an agonist of melatonin receptors MT1 and MT2—attenuated Aβ 25–35 -induced oxidative stress (MDA and ROS) and phosphorylated tau levels in addition to restoring cell viability [ 100 ].…”

RORα Regulates Odontoblastic Differentiation and Mediates the Pro-Odontogenic Effect of Melatonin on Dental Papilla Cells

“…These predominant effects are generally mediated by membrane receptors (MT1 and MT2), nuclear receptors, cytosolic binding sites (MT3 and calmodulin) and mitochondria [ 19 , 20 , 21 ]. Recently, numerous studies have shown that melatonin regulates the development of various tissues and organs, including the skin, hair, bone, liver and the nervous system [ 22 , 23 , 24 , 25 ]. In addition, melatonin has been extensively studied in the oral cavity, such as in bone remodelling, osteointegration of dental implants, periodontal disease and oral cancer; however, the effect of melatonin on tooth development and regeneration has not received sufficient attention [ 26 , 27 , 28 , 29 , 30 ].…”