Neuropharmacological Potential of Diterpenoid Alkaloids

This study provides a narrative review of diterpenoid alkaloids (DAs), a family of extremely important natural products found predominantly in some species of Aconitum and Delphinium (Ranunculaceae). DAs have long been a focus of research attention due to their numerous intricate structures and diverse biological activities, especially in the central nervous system (CNS). These alkaloids originate through the amination reaction of tetra or pentacyclic diterpenoids, which are classified into three categories and 46 types based on the number of carbon atoms in the backbone structure and structural differences. The main chemical characteristics of DAs are their heterocyclic systems containing β-aminoethanol, methylamine, or ethylamine functionality. Although the role of tertiary nitrogen in ring A and the polycyclic complex structure are of great importance in drug-receptor affinity, in silico studies have emphasized the role of certain sidechains in C13, C14, and C8. DAs showed antiepileptic effects in preclinical studies mostly through Na+ channels. Aconitine (1) and 3-acetyl aconitine (2) can desensitize Na+ channels after persistent activation. Lappaconitine (3), N-deacetyllapaconitine (4), 6-benzoylheteratisine (5), and 1-benzoylnapelline (6) deactivate these channels. Methyllycaconitine (16), mainly found in Delphinium species, possesses an extreme affinity for the binding sites of α7 nicotinic acetylcholine receptors (nAChR) and contributes to a wide range of neurologic functions and the release of neurotransmitters. Several DAs such as bulleyaconitine A (17), (3), and mesaconitine (8) from Aconitum species have a drastic analgesic effect. Among them, compound 17 has been used in China for decades. Their effect is explained by increasing the release of dynorphin A, activating the inhibitory noradrenergic neurons in the β-adrenergic system, and preventing the transmission of pain messages by inactivating the Na+ channels that have been stressed. Acetylcholinesterase inhibitory, neuroprotective, antidepressant, and anxiolytic activities are other CNS effects that have been investigated for certain DAs. However, despite various CNS effects, recent advances in developing new drugs from DAs were insignificant due to their neurotoxicity

The effects of CCK-8S on spatial memory and long-term potentiation at CA1 during induction of stress in rats

Objective(s): Cholecystokinin (CCK) has been proposed as a mediator in stress. However, it is still not fully documented what are its effects. We aimed to evaluate the effects of systemic administration of CCK exactly before induction of stress on spatial memory and synaptic plasticity at CA1 in rats. Materials and Methods: Male Wistar rats were divided into 4 groups: the control, the control-CCK, the stress and the stress-CCK. Restraint stress was induced 6 hr per day, for 24 days. Cholecystokinin sulfated octapeptide (CCK-8S) was injected (1.6 µg/kg, IP) before each session of stress induction. Spatial memory was evaluated by Morris water maze test. Long term potentiation (LTP) in Schaffer collateral-CA1 synapses was assessed (by 100 Hz tetanization) in order to investigate synaptic plasticity. Results: Stress impaired spatial memory significantly (

Effect of forced treadmill exercise and blocking of opioid receptors with naloxone on memory in male rats

Background: The forced treadmill running can influence the opioid contents of the brain, through both effects of exercise and the effects of stress caused by coercion. Since opioids can cause negative effects on brain functions, this study aimed to evaluate the effect of forced treadmill exercise and blocking of opioid receptors with naloxone on memory in male rats. Materials and Methods: Experimental groups were the control, the exercise, the naloxone, and the naloxone exercise. The exercise program was treadmill running at 22 m/min at 0° inclination for 50 min/day, 6 days/week, for 4 weeks. Naloxone (1 mg/kg) was injected 5 min before the treadmill running. Morris water maze and passive avoidance learning tests were used for evaluation of memory. Acquisition phase of both tests was performed before interventions, and memory was evaluated 1-day and 1-week after the last session of exercise and treatments. Results: Our data showed that forced exercise impaired performance in passive avoidance learning test (P < 0.05 and P <0.01, 1-day, and 1-week after the last session of exercise and treatments, respectively). Spatial memory was only impaired after 1-week in the exercise group. Naloxone had no significant effect on memory in the control group. However, it improved memory in the exercise group, as there was no significant difference between the control and the naloxone exercise in both tests. Conclusion: The data correspond to the possibility that opioidergic system may have mediatory roles in exercise-induced responses in forced exercise. These roles are likely harmful for memory

The effect of treadmill running on passive avoidance learning in animal model of Alzheimer disease

Background : Alzheimer′s disease was known as a progressive neurodegenerative disorder in the elderly and is characterized by dementia and severe neuronal loss in the some regions of brain such as nucleus basalis magnocellularis. It plays an important role in the brain functions such as learning and memory. Loss of cholinergic neurons of nucleus basalis magnocellularis by ibotenic acid can commonly be regarded as a suitable model of Alzheimer′s disease. Previous studies reported that exercise training may slow down the onset and progression of memory deficit in neurodegenerative disorders. This research investigates the effects of treadmill running on acquisition and retention time of passive avoidance deficits induced by ibotenic acid nucleus basalis magnocellularis lesion. Methods : Male Wistar rats were randomly selected and divided into five groups as follows: Control, sham, Alzheimer, exercise before Alzheimer, and exercise groups. Treadmill running had a 21 day period and Alzheimer was induced by 5 μg/μl bilateral injection of ibotenic acid in nucleus basalis magnocellularis. Results : Our results showed that ibotenic acid lesions significantly impaired passive avoidance acquisition ( P < 0.01) and retention ( P < 0.001) performance, while treadmill running exercise significantly ( P < 0.001) improved passive avoidance learning in NBM-lesion rats. Conclusion : Treadmill running has a potential role in the prevention of learning and memory impairments in NBM-lesion rats

The effect of vitamin E on neuronal apoptosis in hippocampal dentate gyrus in rabbits fed with high-cholesterol diets

Background: Hypercholesterolemia that can increase stress oxidative has destructive effects on brain functions. Vitamin E is a powerful antioxidant and its effects on decrement of oxidative stress in the diseases such as Alzheimer′s and hypercholesterolemia are demonstrated. The aim of this study was evaluation of the effects of vitamin E on the level of neuronal apoptosis in granular layer of dentate gyrus in the rabbits that fed with high-cholesterol diet. Materials and Methods: Male New Zealand white rabbits were divided into the control, the Vitamin E (50 mg/kg; gavage), the high-cholesterol diet (containing 2% cholesterol), and the high-cholesterol diet-vitamin E groups. Serum levels of cholesterol, LDL, and HDL, before and after the regimen for 6 weeks, were measured. Then, the rabbits for immunohistochemical staining (TUNEL Test) and evaluation of neuronal apoptosis in dentate gyrus of hippocampal formation were anesthetized and brains were dissected. Results: Results showed that after the regimens, serum levels of cholesterol, LDL, and HDL in the cholesterol receiving groups were increased significantly (P < 0.05). Histological results demonstrated that neuronal apoptosis in the dentate gyrus of the high-cholesterol diet group was increased significantly (P < 0.05) comparing to the control group; however, vitamin E decreased apoptosis as there wasn′t any significant differences between the high-cholesterol diet-vitamin E and control groups. Conclusions: Present results showed that consumption of high-cholesterol diets through hypercholesterolemia and its complication can induce neuronal death in hippocampus and probable resulting cognition disorders; however, vitamin E has neuroprotective effects and prevents neuronal apoptosis significantly

Electrical stimulation of prelymbic with different currents intensities on morphine induced spatial memory deficit in rats

Background: The medial prefrontal cortex (mPFC) is a part of brain reward system involved in cognitive functions such as learning and memory. Previous studies showed that electrical stimulation of prelymbic produced different effects on morphine-induced condition place preference. In this study, we investigated the electrical stimulation with different current intensities on spatial memory in rats. Materials and Methods: In this study, male Wister rats weighing approximately 200–300 g were used. The effect of prelymbic electrical stimulation with 25 and 150 μA currents intensities in healthy and addicted rats on spatial memory was studied. Spatial memory was investigated using the Morris water maze test in addicted rats after 9 days of electrical stimulation. Results: Our findings have shown that morphine reduces the memory and learning, whereas the present results indicated that electrical stimulation of prelymbic area with current intensity of the 25 μA shortened the time and distance to reach to platform that indicated improvement in spatial memory on addicted rats. Whereas the electrical stimulation of prelymbic area with the current intensity of 150 μA has special weakening effects on spatial memory and prolongs the time and distance to reach the platform. Conclusions: The electrical stimulations of prelymbic with 25 μA current intensity improved the spatial memory in addicted rats while with 150 μA current intensity weakened spatial memory in rats. It is possible that increase in the release of some neurotransmitters reverses the effect of morphine on spatial memory

The effect of red grape juice on Alzheimer′s disease in rats

Background: Alzheimer′s disease is a neurodegenerative disease appearing as a result of free radicals and oxidative stress. Antioxidants agents boost memory and control Alzheimer′s disease. Since red grape juice contains antioxidant agents, its effects on speed of learning and improvement of memory was studied in Alzheimer′s rats. Materials and Methods: Alzheimer′s model was induced by bilateral infusion of streptozocine into lateral ventricles of brain of male rats. Rats drank 10% red grape juice for 21 days. Passive avoidance learning test was used for measuring memory and learning in rats. Results: Our results showed that learning and memory in STZ-group decreased significantly compared to Sham group. However, intake of red grape juice increased speed of learning and improvement of memory in Alzheimer′s rats. Conclusions: Our results suggest that there are active ingredients in red grape juice, which probably have therapeutic and preventive effects on cognitive impairments in Alzheimer′s disease

Effects of amitriptyline and fluoxetine on synaptic plasticity in the dentate gyrus of hippocampal formation in rats

Background: Several studies have been shown that antidepressant drugs have contradictory effects on cognitive processes. Therefore, the aim of this study was to investigate the effects of amitriptyline and fluoxetine on synaptic plasticity in the dentate gyrus (DG) of the hippocampal formation in rat. Materials and Methods: Experimental groups were the control, the fluoxetine, and amitriptyline. The rats were treated for 21 days and then, paired pulse facilitation/inhibition (PPF/I) and long-term potentiation (LTP) in perforant path-DG synapses were assessed (by 400 Hz tetanization). Field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude were measured. Results: The results of PPF/I showed that PS amplitude ratios were increased in 10-70 ms inter-stimulus intervals in the amitriptyline group compared to the control group. In the fluoxetine group, EPSP slope ratios were decreased in intervals 30, 40, and 50 ms inter-stimulus intervals compared to the control group. The PS-LTP was significantly lower in the fluoxetine and the amitriptyline groups with respect to the control group. Conclusion: The results showed that fluoxetine and amitriptyline affect synaptic plasticity in the hippocampus and these effects is probably due to the impact on the number of active neurons