Effects of morphine on conditioned place preference and pain are independent of uptake­2.

Morphine changes neurotransmitter release, including norepinephrine, dopamine, and serotonin. Decynium­22 (D22) inhibits an alternative neurotransmitter removal pathway, namely uptake­2. Uptake­2 includes plasma membrane monoamine transporter (PMAT) and organic cation transporters that have a low affinity, but high capacity for uptake of various monoamines such as norepinephrine, dopamine, and serotonin. This study was done to assess the effect of uptake­2 inhibition on morphine­induced conditioned place preference (CPP) and analgesia. In this study, the effects of morphine and/or D22 on CPP were evaluated following intraperitoneal injection in mice. Afterward, changes in motor activity were evaluated by the open field test. Using the tail­flick model, the effects of D22 and/or morphine were evaluated on the pain threshold. The results showed that 20 mg/kg of morphine induced a place preference response. D22, at the dose of 0.03 mg/kg, caused place avoidance, while at the dose of 0.3 mg/kg, it produced a notable place preference response. Co­administration of D22 and morphine showed that morphine reversed the CPP aversion induced by D22 at the lowest dose. Motor activity did not alter. In the tail­flick test, morphine, at the dose of 3 mg/kg but not 1 mg/kg, increased the pain threshold. D22 induced significant analgesic responses. Co­administration of D22 and morphine caused considerable analgesic effects. The findings revealed that D22 induced both conditioned aversion and preference depending on the dose while morphine induced CPP. Both drugs produced analgesia.

Evaluating the Protective Effects of Thymoquinone on Methamphetamine-induced Toxicity in an In Vitro Model Based on Differentiated PC12 Cells.

Methamphetamine (Meth) is a highly addictive stimulant. Its potential neurotoxic effects are mediated through various mechanisms, including oxidative stress and the initiation of the apoptotic process. Thymoquinone (TQ), obtained from Nigella sativa seed oil, has extensive antioxidant and anti-apoptotic properties. This study aimed to investigate the potential protective effects of TQ against Meth-induced toxicity by using an in vitro model based on nerve growth factor-differentiated PC12 cells. Cell differentiation was assessed by detecting the presence of a neuronal marker with flow cytometry. The effects of Meth exposure were evaluated in the in vitro neuronal cell-based model via the determination of cell viability (in an MTT assay) and apoptosis (by annexin/propidium iodide staining). The generation of reactive oxygen species (ROS), as well as the levels of glutathione (GSH) and dopamine, were also determined. The model was used to determine the protective effects of 0.5, 1 and 2 µM TQ against Meth-induced toxicity (at 1 mM). The results showed that TQ reduced Meth-induced neurotoxicity, possibly through the inhibition of ROS generation and apoptosis, and by helping to maintain GSH and dopamine levels. Thus, the impact of TQ treatment on Meth-induced neurotoxicity could warrant further investigation.

TRPA1 as a promising target in ischemia/reperfusion: A comprehensive review.

Ischemic disorders, including myocardial infarction, cerebral ischemia, and peripheral vascular impairment, are the main common reasons for debilitating diseases and death in Western cultures. Ischemia occurs when blood circulation is reduced in tissues. Reperfusion, although commanded to return oxygen to ischemic tissues, generates paradoxical tissue responses. The responses include generating reactive oxygen species (ROS), stimulating inflammatory responses in ischemic organs, endoplasmic reticulum stress, and the expansion of postischemic capillary no-reflow, which intensifies organ damage. Multiple pathologic processes contribute to ischemia/reperfusion; therefore, targeting different pathologic processes may yield an effective therapeutic approach. Transient Receptor Potential A1 (TRPA1) belongs to the TRP family of ion channels, detects a broad range of chemicals, and promotes the transduction of noxious stimuli, e.g., methylglyoxal, ROS, and acrolein effects are attributed to the channel's sensitivity to intracellular calcium elevation or phosphoinositol phosphate modulation. Hypoxia and ischemia are associated with oxidative stress, which activates the TRPA1 channel. This review describes the role of TRPA1 and its related mechanisms that contribute to ischemia/reperfusion. Relevant articles were searched from PubMed, Scopus, Web of Sciences, and Google Scholar electronic databases, up to the end of August 2023. Based on the evidence presented here, TRPA1 may have protective or deteriorative functions during the ischemia/reperfusion process. Its function depends on the activation level, the ischemic region, the extent of lesions, and the duration of ischemia.

The role of ATP-binding cassette transporter G1 (ABCG1) in Alzheimer's disease: A review of the mechanisms.

The maintenance of cholesterol homeostasis is essential for central nervous system function. Consequently, factors that affect cholesterol homeostasis are linked to neurological disorders and pathologies. Among them, ATP-binding cassette transporter G1 (ABCG1) plays a significant role in atherosclerosis. However, its role in Alzheimer's disease (AD) is unclear. There is inconsistent information regarding ABCG1's role in AD. It can increase or decrease amyloid ß (Aß) levels in animals' brains. Clinical studies show that ABCG1 is involved in AD patients' impairment of cholesterol efflux capacity (CEC) in the cerebrospinal fluid (CSF). Lower Aß levels in the CSF are correlated with ABCG1-mediated CEC dysfunction. ABCG1 modulates α-, ß-, and γ-secretase activities in the plasma membrane and may affect Aß production in the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) cell compartment. Despite contradictory findings regarding ABCG1's role in AD, this review shows that ABCG1 has a role in Aß generation via modulation of membrane secretases. It is, however, necessary to investigate the underlying mechanism(s). ABCG1 may also contribute to AD pathology through its role in apoptosis and oxidative stress. As a result, ABCG1 plays a role in AD and is a candidate for drug development.

Effects of telmisartan on metabolic syndrome components: a comprehensive review.

Telmisartan is an antagonist of the angiotensin II receptor used in the management of hypertension (alone or in combination with other antihypertensive agents. It belongs to the drug class of angiotensin II receptor blockers (ARBs). Among drugs of this class, telmisartan shows particular pharmacologic properties, including a longer half-life than any other angiotensin II receptor blockers that bring higher and persistent antihypertensive activity. In hypertensive patients, telmisartan has superior efficacy than other antihypertensive drugs (losartan, valsartan, ramipril, atenolol, and perindopril) in controlling blood pressure, especially towards the end of the dosing interval. Telmisartan has a partial PPARγ-agonistic effect whilst does not have the safety concerns of full agonists of PPARγ receptors (thiazolidinediones). Moreover, telmisartan has an agonist activity on PPARα and PPARδ receptors and modulates the adipokine levels. Thus, telmisartan could be considered as a suitable alternative option, with multi-benefit for all components of metabolic syndrome including hypertension, diabetes mellitus, obesity, and hyperlipidemia. This review will highlight the role of telmisartan in metabolic syndrome and the main mechanisms of action of telmisartan are discussed and summarized. Many studies have demonstrated the useful properties of telmisartan in the prevention and improving of metabolic syndrome and this well-tolerated drug can be greatly proposed in the treatment of different components of metabolic syndrome. However, larger and long-duration studies are needed to confirm these findings in long-term observational studies and prospective trials and to determine the optimum dose of telmisartan in metabolic syndrome.

The role of transient receptor potential (TRP) channels in phagocytosis: A comprehensive review.

When host cells are exposed to foreign particles, dead cells, or cell hazards, a sophisticated process called phagocytosis begins. During this process, macrophages, dendritic cells, and neutrophils engulf the target by expanding their membranes. Phagocytosis of apoptotic cells is called efferocytosis. This process is of significant importance as billions of cells are eliminated daily without provoking inflammation. Both phagocytosis and efferocytosis depend on Ca2+ signaling. A big family of Ca2+ permeable channels is transient receptor potentials (TRPs) divided into nine subfamilies. We aimed to review their roles in phagocytosis. The present review article shows that various TRP channels such as TRPV1, 2, 3, 4, TRPM2, 4, 7, 8, TRPML1, TRPA1, TRPC1, 3, 5, 6 have roles at various stages of phagocytosis. They are involved in the phagocytosis of amyloid ß, α-synuclein, myelin debris, bacteria, and apoptotic cells. In particular, TRPC3 and TRPM7 contribute to efferocytosis. These effects are mediated by changing Ca2+ signaling or targeting intracellular enzymes such as Akt. In addition, they contribute to the chemotaxis of phagocytic cells towards targets. Although a limited number of studies have assessed the role of TRP channels in phagocytosis and efferocytosis, their findings indicate that they have critical roles in these processes. In some cases, their ablation completely abolished the phagocytic function of the cells. As a result, TRP channels are potential targets for developing new therapeutics that modulate phagocytosis.

An overview on the protective effects of ellagic acid against heavy metals, drugs, and chemicals.

Ellagic acid (EA) is a polyphenol extracted from many plants. EA modulates inflammatory mediators via antioxidant mechanisms, such as catalase (CAT) activities, superoxide dismutase (SOD), enhancement, increase in glutathione (GSH), and lipid peroxidation (LPO) suppression. EA has anti-apoptotic properties that are thought to be mediated by regulating the expression of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), and caspase-3. In this article, we surveyed the literature dealing with the protective effects of EA against different heavy metals, drugs, and natural toxins. The findings indicated that EA has remarkable protective properties against various toxicants. Its protective effects were mostly mediated via normalizing lipid metabolism, oxidative stress, and inflammatory mediators, for example, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1ß. The results of this study showed that EA has significant protective effects against a varied range of compounds, either chemical or natural. These effects are mainly mediated via intensifying the antioxidant defense system. However, other mechanisms such as inhibition of inflammatory responses and suppression of apoptosis are important.

Dietary carotenoids to improve hypertension.

Hypertension is one of the major risk factors for cardiovascular diseases and the main reason for premature death in older adults. Although antihypertensive medications have been used frequently, hypertension prevalence has increased in the last decade. Lifestyle improvement is a cornerstone of hypertension prevention and control. High dietary consumptions of fruits and vegetables are linked to reduced risks of high blood pressure. Carotenoids are natural tetraterpene pigments produced by bacteria, fungi, algae, some animals, and various plants. Because of their high pharmacological potential and safety, they have been mentioned as unique therapeutic agents for a diverse range of diseases. Carotenoids modulate high blood pressure. They also have several additional benefits for the cardiovascular system, including antioxidative, anti-inflammatory, anti-atherogenic, and antiplatelet effects. They improve endothelial function and metabolic profile, as well. In the present article, we reviewed the literature data regarding carotenoids' influence on hypertension in both preclinical and clinical studies. Furthermore, we reviewed the underlying mechanisms associated with antihypertensive properties derived from in vitro and in vivo studies. Suppressing reactive oxygen species (ROS) production, Inhibiting angiotensin-II, endothelin-1, and oxidized low-density lipoprotein; and also nitric oxide enhancement are some of the mechanisms by which they lower blood pressure. The present article indicated that astaxanthine, ß-carotene, bixin, capsanthin, lutein, crocin, and lycopene have antihypertensive properties. Having significant antioxidant properties, they can decrease high blood pressure and concomitant comorbidities.

Efficacy of orally administered montmorillonite in myoglobinuric acute renal failure model in male rats.

Objectives: Acute kidney injury can be associated with serious consequences and therefore early treatment is critical to decreasing mortality and morbidity rate. We evaluated the effect of montmorillonite, the clay with strong cation exchange capacity, on the AKI model in rats. Materials and Methods: Glycerol (50% solution, 10 ml/kg) was injected in the rat hind limbs to induce AKI. 24 hr after induction of acute kidney injury, the rats received oral doses of montmorillonite (0.5 g/kg or 1 g/kg), or sodium polystyrene sulfonate (1 g/kg) for three consecutive days. Results: Glycine induced acute kidney injury in rats with high levels of urea (336.60± 28.19 mg/dl), creatinine (4.10± 0.21 mg/dl), potassium (6.15 ± 0.28 mEq/L), and calcium (11.52 ± 0.19 mg/dl). Both doses of montmorillonite (0.5 and 1 g/kg) improved the serum urea (222.66± 10.02 and 170.20±8.06, P<0.05), creatinine (1.86±0.1, 2.05± 0.11, P<0.05), potassium (4.68 ± 0.4, 4.73 ± 0.34, P<0.001) and calcium (11.15 ± 0.17, 10.75 ± 0.25, P<0.01) levels. Treatment with montmorillonite especially at a high dose reduced the kidney pathological findings including, tubular necrosis, amorphous protein aggregation, and cell shedding into the distal and proximal tubule lumen. However, administration of SPS could not significantly decrease the severity of damages. Conclusion: According to the results of this study, as well as the physicochemical properties of montmorillonite, such as high ion exchange capacity and low side effects, montmorillonite can be a low-cost and effective treatment option to reduce and improve the complications of acute kidney injury. However, the efficacy of this compound in human and clinical studies needs to be investigated.

Effects of multiple doses of montmorillonite, alone and in combination with activated charcoal, on the toxicokinetics of a single dose of digoxin in rats.

Objectives: A narrow margin between the therapeutic and toxic doses of digoxin can result in an increased incidence of toxicity. Since digoxin has an enterohepatic cycle, multiple oral doses of absorbents like montmorillonite may be useful in the treatment of digoxin toxicity. Materials and Methods: In this study, 4 groups of 6 rats received intraperitoneal digoxin (1 mg/kg), and half an hour later, distilled water (DW) or oral adsorbents, including montmorillonite (1 g/kg), activated charcoal (1 g/kg) (AC) alone or in combination in the ratio of 70:30. Half of the mentioned doses were also gavaged at 3 and 5.5 hr after digoxin injection. The serum level of digoxin, biochemical factors, and activity score were assessed during the experiment. Three control groups only received DW, montmorillonite, or AC. Results: All adsorbents were able to significantly decrease the serum level of digoxin compared to the digoxin+DW group (P<0.01). Only montmorillonite reversed the digoxin-induced hyperkalemia (P<0.05). Multiple dose administration of adsorbents also significantly reduced the digoxin area under the curve and half-life and increased digoxin clearance (P<0.05). However, there was no significant difference in the kinetic parameters between groups that received digoxin plus adsorbents. Conclusion: Multiple-dose of montmorillonite reversed digoxin toxicity and reduced serum digoxin levels by increasing the excretion and reducing the half-life. Montmorillonite has also corrected digoxin-induced hyperkalemia. Based on the findings, a multiple-dose regimen of oral montmorillonite could be a suitable candidate for reducing the toxicity issue associated with drugs like digoxin that undergo some degree of enterohepatic circulation.

The role of the ATP-Binding Cassette A1 (ABCA1) in neurological disorders: a mechanistic review.

INTRODUCTION: Cholesterol homeostasis is critical for normal brain function. It is tightly controlled by various biological elements. ATP-binding cassette transporter A1 (ABCA1) is a membrane transporter that effluxes cholesterol from cells, particularly astrocytes, into the extracellular space. The recent studies pertaining to ABCA1's role in CNS disorders were included in this study. AREAS COVERED: In this comprehensive literature review, preclinical and human studies showed that ABCA1 has a significant role in the following diseases or disorders: Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, neuropathy, anxiety, depression, psychosis, epilepsy, stroke, and brain ischemia and trauma. EXPERT OPINION: ABCA1 via modulating normal and aberrant brain functions such as apoptosis, phagocytosis, BBB leakage, neuroinflammation, amyloid ß efflux, myelination, synaptogenesis, neurite outgrowth, and neurotransmission promotes beneficial effects in aforementioned diseases. ABCA1 is a key molecule in the CNS. By boosting its expression or function, some CNS disorders may be resolved. In preclinical studies, liver X receptor agonists have shown promise in treating CNS disorders via ABCA1 and apoE enhancement.

The potential of CYP46A1 as a novel therapeutic target for neurological disorders: An updated review of mechanisms.

Cholesterol is a key component of the cell membrane that impacts the permeability, fluidity, and functions of membrane-bound proteins. It also participates in synaptogenesis, synaptic function, axonal growth, dendrite outgrowth, and microtubule stability. Cholesterol biosynthesis and metabolism are in balance in the brain. Its metabolism in the brain is mediated mainly by CYP46A1 or cholesterol 24-hydroxylase. It is responsible for eliminating about 80% of the cholesterol excess from the human brain. CYP46A1 converts cholesterol to 24S-hydroxycholesterol (24HC) that readily crosses the blood-brain barrier and reaches the liver for the final elimination process. Studies show that cholesterol and 24HC levels change during neurological diseases and conditions. So, it was hypothesized that inhibition or activation of CYP46A1 would be an effective therapeutic strategy. Accordingly, preclinical studies, using genetic and pharmacological interventions, assessed the role of CYP46A1 in main neurodegenerative disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, multiple sclerosis, spinocerebellar ataxias, and amyotrophic lateral sclerosis. In addition, its role in seizures and brain injury was evaluated. The recent development of soticlestat, as a selective and potent CYP46A1 inhibitor, with significant anti-seizure effects in preclinical and clinical studies, suggests the importance of this target for future drug developments. Previous studies have shown that both activation and inhibition of CYP46A1 are of therapeutic value. This article, using recent studies, highlights the role of CYP46A1 in various brain diseases and insults.

Cannabidiol goes nuclear: The role of PPARγ.

BACKGROUND: Cannabidiol (CBD) is one of the main phytocannabinoids found in Cannabis sativa. In contrast to Δ9-tetrahydrocannabinol, it has a low affinity for cannabinoid receptors CB1 and CB2, thereby it does not induce significant psychoactive effects. However, CBD may interact with other receptors, including peroxisome proliferator-activated receptor gamma (PPARγ). CBD is a PPARγ agonist and changes its expression. There is considerable evidence that CBD's effects are mediated by its interaction with PPARγ. So, we reviewed studies related to the interaction of CBD and PPARγ. METHODS: In this comprehensive literature review, the term 'cannabidiol' was used in combination with the following keywords including 'PPARγ', 'Alzheimer's disease', 'Parkinson's disease', 'seizure', 'multiple sclerosis', 'immune system', 'cardiovascular system', 'cancer', and 'adipogenesis'. PubMed, Web of Science, and Google Scholar were searched until December 20, 2022. A total of 78 articles were used for the reviewing process. RESULTS: CBD, via activation of PPARγ, promotes significant pharmacological effects. The present review shows that the effects of CBD on Alzheimer's disease and memory, Parkinson's disease and movement disorders, multiple sclerosis, anxiety and depression, cardiovascular system, immune system, cancer, and adipogenesis are mediated, at least in part, via PPARγ. CONCLUSION: CBD not only activates PPARγ but also affects its expression in the body. It was suggested that the late effects of CBD are mediated via PPARγ activation. We suggested that CBD's chemical structure is a good backbone for developing new dual agonists. Combining it with other chemicals enhances their biological effectiveness while reducing their dosage. The present study indicated that PPARγ is a key target for CBD, and its activation by CBD should be considered in all future studies.

Inhibition of Drp1-dependent mitochondrial fission by natural compounds as a therapeutic strategy for organ injuries.

Mitochondria are morphologically dynamic organelles frequently undergoing fission and fusion processes that regulate mitochondrial integrity and bioenergetics. These processes are considered critical for cell survival. The mitochondrial fission process regulates mitochondrial biogenesis and mitophagy. It is associated with apoptosis, while mitochondrial fusion controls the accurate distribution of mitochondrial DNA and metabolic substances across the mitochondria. Excessive mitochondrial fission results in mitochondrial structural changes, dysfunction, and cell damage. Accumulating evidence demonstrates that mitochondrial dynamics affect neurodegenerative and cardiovascular diseases along with several other diseases. Biological molecules regulating the process of mitochondrial fission are potential targets for developing therapeutic agents. Many natural products target the dynamin-related protein 1 (Drp1)-dependent mitochondrial fission pathway, and their inhibitory effects ameliorate mitochondrial fragmentation. In this article, we reviewed the research literature that describes Drp1-dependent inhibition as a mechanism for the protective effects of natural compounds.

The protective effects of rutin on the liver, kidneys, and heart by counteracting organ toxicity caused by synthetic and natural compounds.

Rutin is a flavonoid present in many plant species. Because of its antioxidant, anti-inflammatory, and antiapoptotic properties, rutin is of interest for its potential protective effects against toxic agents. The hepatoprotective, renoprotective, and cardioprotective effects of rutin are reviewed. The antioxidant effects of rutin are elicited by enhancing antioxidant enzymes such as GST, GGT, CAT, GPx, SOD, and GR, activating the Nrf2/HO-1 pathway, elevating GSH content, and the reduction in MDA. The anti-inflammatory effects of rutin are mediated by the inhibition of IL-1ß, IL-6, TGF-ß1, COX-2, iNOS, TLR4, and XO. Rutin exerted its antiapoptotic effects by inhibition of free radicals, caspase-3/-7/-9, hsp70, HMGB1, and p53, and the elevation of the antiapoptotic protein Bcl-2. Rutin has potential therapeutic effectiveness against several toxicants, and its beneficial effects are more than likely mediated by its antioxidant, anti-inflammatory, and/or antiapoptotic property.

The blockade of transient receptor potential ankyrin 1 (TRPA1) protects against PTZ-induced seizure.

Treatment of epilepsy remains a major problem as some epileptic patients do not respond to the current therapeutics. Transient receptor potential ankyrin 1 (TRPA1) belongs to the TRP channels and has diverse physiological functions in the body. Considering its physiological properties, we aimed to evaluate its role in two experimental models of epilepsy, including pentylenetetrazol (PTZ)-induced acute seizure and PTZ-evoked kindling. Furthermore, the TRPA1 protein levels were assessed in the cerebral cortex, hippocampus, and cerebellum after seizure induction. Three groups of Wistar rats received acute intraperitoneal injection of pentylenetetrazol (PTZ, 85 mg/kg). The groups received intraventricular injections of vehicle (dimethyl sulfoxide, Tween 80, and sterile 0.9% saline), valproate (30 µg/rat), or HC030031 (TRPA1 antagonist, 14 µg/rat) before PTZ injection. In the PTZ-induced kindling model, PTZ was administrated 35 mg/kg every other day for 24 days. PTZ gradually provoked seizure-related behaviors. After experiments, the TRPA1 levels in the brain were assessed using western blot. The results showed that HC030031 reduced the median of seizure scores and S5 duration while increasing S2 and S5 latencies in acute and kindling models. The anticonvulsant effect of HC030031 was comparable with valproate as a standard anticonvulsant drug. Furthermore, induction of seizure, either acute or kindling, enhanced TRPA1 levels in the cerebral cortex, hippocampus, and cerebellum that were prevented by HC030031 or valproate administration. The results of this study showed that HC030031 as a TRPA1 receptor antagonist promoted a significant anticonvulsant effect comparable with valproate. Both drugs prevented TRPA1 upregulation during seizures. These findings imply that TRPA1 is a potential target in treating epilepsy.

Involvement of the transient receptor potential A1 in morphine-induced conditioned place preference and physical dependence in mice.

The main side effects of opioid use are physiological and psychological dependence. The transient receptor potential channels, including transient receptor potential ankyrin 1 (TRPA1), are involved in various neurological disorders. We aimed to evaluate the effect of TRPA1 inhibition on morphine-induced conditioned place preference (CPP) and physical dependence. For induction of CPP, morphine (10 and 20 mg/kg) was administrated for four consecutive days to male BALB/c mice. The effects of HC030031 (TRPA1 antagonist, 10, 25, and 50 mg/kg) on the expression and reinstatement of morphine-induced CPP were evaluated. For induction of physical dependence, morphine was injected three times a day for 3 days. Withdrawal-related behaviors such as jumping and defecation were precipitated by the administration of naloxone to morphine-dependent mice. The effect of HC030031 on jumping and defecation was assessed. The results showed that 20 mg/kg of morphine elicited a significant CPP. HC030031 reduced the expression of morphine CPP without any change in the locomotor activity. It also decreased the reinstatement of morphine CPP. HC030031 mitigated morphine withdrawal via reducing jumping and defecation. The present study demonstrated that HC030031 decreased morphine-associated CPP and physical dependence. It is presumed that TRPA1 has interaction with the main pharmacological effects of morphine.

Resolvin D1: A key endogenous inhibitor of neuroinflammation.

After the initiation of inflammation, a series of processes start to resolve the inflammation. A group of endogenous lipid mediators, namely specialized pro-resolving lipid mediators is at the top list of inflammation resolution. Resolvin D1 (RvD1), is one of the lipid mediators with significant anti-inflammatory properties. It is produced from docosahexaenoic acid (omega-3 polyunsaturated fatty acid) in the body. In this article, we aimed to review the most recent findings concerning the pharmacological effects of RvD1 in the central nervous system with a focus on major neurological diseases and dysfunctions. A literature review of the past studies demonstrated that RvD1 plasma level changes during mania, depression, and Parkinson's disease. Furthermore, RVD1 and its epimer, aspirin-triggered RvD1 (AT-RvD1), have significant therapeutic effects on experimental models of ischemic and traumatic brain injuries, memory dysfunction, pain, depression, amyotrophic lateral sclerosis, and Alzheimer's and Parkinson's diseases. Interestingly, the beneficial effects of RvD1 and AT-RvD1 were mostly induced at nanomolar and micromolar concentrations implying the significant potency of these lipid mediators in treating diseases with inflammation.