The role of apitoxin in alleviating propionic acid-induced neurobehavioral impairments in rat pups: The expression pattern of Reelin gene
Graphical abstract
Introduction
Approximately 3% of neurobehavioral disorders are directly induced by environmental exposures to toxicants and about 25% of these conditions are induced via interactions between inherited susceptibilities and environmental pollutants [1]. Propionic acid (PPA) is a short chain fatty acid and the main end product of numerous enteric gut bacteria [2], [3]. PPA is commonly utilized as a food preservative due to its effective preservative activity, mold inhibition and bactericidal properties. Also, PPA is an additive used in dairy products, poultry litter, livestock rations, and drinking water [4].
By both active and passive means, PPA easily crosses both the gut–blood and blood–brain barriers [5]. Brain exposure to PPA may disturb various neurophysiological processes, including neurotransmitter release, gene expression, mitochondrial function, immune modulation, gap junction gating, and behavior [6], [7]. In rat models, propionic acidemia resulted from either central (i.e., intraventricular) or peripheral (i.e., intraperitoneal or oral) administration of PPA have revealed diverse behaviors and brain markers including repetitive behaviors, impairments in cognition and social behavior, increases in oxidative stress markers, reductions in glutathione, alterations of brain phospholipids/acylcarnitines and neuroinflammation [8], [9], [10], [11], [12], [13].
Therapies have been studied to repair or guard against various neurobehavioral disorders. Various vertebrate and arthropod venoms from snakes, toads, frogs, spiders, scorpions, bees, wasps, and ants have shown pharmacological applications [14]. In particular, apitoxin (bee venom; BV) is a very complex mixture of about 18 active components, including enzymes, active peptides, and amines containing melittin, histamine, polyamines, phospholipase A2, and catecholamines [15]. The radioprotective, antimutagenic, pain relieving, anti-inflammatory, antihyperalgesic, anticancer and antinociceptive effects of BV have been documented [16], [17], [18], [19], [20].
Recently, the BV role in combating neurodegenerative ailments of the central nervous system (CNS) has been documented in many clinical studies [20], [21], [22]. Furthermore, in a 1-methyl-4-phenyl-1,2,3,6-tetrahy dropyridine (MPTP)-induced mouse model, BV acupuncture displayed an obvious neuroprotective action [22]. Moreover, BV might exert a direct neuroprotective effect on SH-SY5Y human neuroblastoma cells against MPP+-induced apoptotic cell death [23]. Yet, there are no studies demonstrating the protective or therapeutic role of BV in PPA-induced neurobehavioral disorders. Our earlier study showed that BV provides beneficial effects by diminishing PPA-induced oxidative stress, neuronal death, and DNA damage in the brains of rat pups [11].
Reelin is a glycoprotein secreted in the cerebral cortex and hippocampus from Cajal-Retzius cells and it acts as a regulator of many phases of laminar formation [24], [25]. Many studies have documented altered Reelin expression in rodents with cognitive dysfunction related to neuropsychiatric disorders [26], [27]. Recent genome screening studies using both a case-control and a family-based design have provided supporting evidence for the linkage/association between Reelin gene variants and either maternal deprivation or autistic disorder [28], [29]. Furthermore, post-mortem autistic brain biochemical analyses have implicated Reelin in the pathogenesis of autism [29], [30].
The specific aims of the current study were to verify whether BV presents a potential protective or therapeutic treatment against PPA-induced neural markers and behavioral performance, and to evaluate the expression pattern of Reelin gene in PPA- intoxicated rat pup brain.
Section snippets
Tested compounds and chemicals
Egyptian honey bee venom (BV) (Apis mellifera lamarckii) was obtained in lyophilized pure form from the Department of Bee Research, Plant Protection Institute, Ministry of Agriculture, Egypt. It was stored, desiccated at 4 °C and dissolved in sterile phosphate buffer saline directly before use (PBS; pH 7.2). PPA was purchased from Alpha Chemika, Mumbai, India. Enzyme-linked immunosorbent assays (ELISA) using commercial kits were applied to estimate dopamine (CUSABIO, P.R. China, Catalogue No.
Exploratory activity
In the open field test, the PPA-treated rat pups showed a significant decrease in head-dip behavior compared with the control group (2.7 ± 0.3 vs 5.0 ± 0.3, respectively, Fig. 1). In contrast, the BV-treated and concomitant protective and therapeutic-treated rat pups (BV/PPA/BV) showed a non-significant increase in the number of head-dips, 5.8 ± 0.3 and 5.3 ± 0.2, respectively, compared with the control group. Head-dip behavior showed a small decrease in either therapeutic or protective-treated pups,
Discussion
Arthropod venoms have a composite collection of biological active molecules with a vast range of systemic effects. Recent animal studies of the peptides and acylpolyamines isolated from arthropod venoms have revealed the high efficacy of these molecules for the treatment of a variety of neurodegenerative diseases such as epilepsy, Parkinson’s, Alzheimer’s, chronic pain and anxiety disorders [45].
BV is arthropod venom with various therapeutic uses as an antinociceptive and anti-inflammatory
Conclusion
Taken together, our data clearly indicate that BV might be a beneficial compound for developing effective protective and therapeutic interventions against neurobehavioral disorders especially lack of exploration, social and learning aquisition, alterations in neurotransmitter levels and Reelin gene downregulation induced by PPA intoxication in rat pups. In addition, these data contribute to the validity of the rat model to improve the research of neurobehavioral disorders. Further studies are
Competing interests
The authors declare that they have no competing interests.
Acknowledgments
This research project was supported by a grant from the “Research Centre of the Female Scientific and Medical Colleges”, Deanship of Scientific Research, King Saud University. The authors thank Prof. Dr. John Vandenberg, Division Director at U.S. Environmental Protection Agency and professor at Duke University, for scientific reviewing and English language editing.
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