Neuroprotective Effects Of N-acetylcysteine Research Articles

Fluimucil as a neuroprotective, is there anything new? Bibliometric study from 1996 to 2024

Introduction Fluimucil, also known as N-acetylcysteine (NAC), has been used as a medicinal drug for treating Alzheimer’s and Parkinson’s disease. Recent research has shown NAC’s potential as a neuroprotective agent, preventing oxidative damage and promoting neurodegenerative treatment. This study conducted bibliometric analysis of articles related to NAC use, identifying research trends, current trends, and correlations between research and institutions. The findings can help identify unpublished research and guide future research strategies. This research not only provides public interest in NAC research but also offers valuable insights for future research. Methods In this work, a literature review methodology is employed to gather data from the Scopus database using the keywords fluimucil, nac, n-acetylcystein, and neuroprotective. Data were analyzed using Biblioshiny and VOSviewer software to produce visualizations and bibliometric maps. We conducted quantitative and qualitative analysis. Results The research trend found are Documents by Year, Documents by Author, Documents by Affiliations, Documents by country or territory, Documents by funding sponsor, Factorial Map Of The Documents With The Highest Contributes, Documents by Subject Area, Network Visualization, Overlay visualization of scopus database using Vosviewer, Density Visualization, Thematic Map, and Qualitative Analysis. Conclusions Research on the neuroprotective effects of N-acetylcysteine (NAC) or fluimucil has several limitations and strengths. It uses quantitative and qualitative analysis to identify research trends and mechanisms of NAC action. However, the data may be biased and the methodology may differ. The study has significant potential for future research, particularly in treating neurodegenerative diseases like Parkinson and Alzheimer. It also contributes to the understanding of NAC mechanisms.

Neuroprotective Effect of N-acetylcysteine Against Monocrotophos-Induced Oxidative Stress in Different Brain Regions of Rats.

Monocrotophos (MCP) is systemic organophosphate insecticide used against crop pests. It is reported to cause mammalian toxicity through both acute and chronic exposure. In the present study, we have shown the protective role of N-acetylcysteine (NAC) against MCP-induced oxidative stress in frontal cortex, corpus striatum and hippocampus brain regions of rats. Male Albino Wistar rats were divided into control, NAC-treated, MCP and NAC + MCP-treated groups. An oral dose of MCP (0.9mg/kg b.wt) and NAC (200mg/kg b.wt) was administered for 28days. Results showed an increase in lipid peroxidation (LPO) and protein oxidation followed by decreased antioxidant enzymes after 28days of MCP exposure. Histopathological analysis showed that monocrotophos exposure caused neurodegenerative changes as evident by neurons with dystrophic changes in the form of shrunken hyperchromatic nuclei in all the regions of the rat brain. N-acetylcysteine supplementation to MCP-treated rats showed a reduction in oxidative stress and ameliorated cellular alterations in all of the three regions. The results of the study indicate that N-acetylcysteine offers neuroprotection by improving antioxidant response and decreasing oxidative stress in different regions of the rat brain.

N-Acetylcysteine Rescues Hippocampal Oxidative Stress-Induced Neuronal Injury via Suppression of p38/JNK Signaling in Depressed Rats.

Progression of neuronal deterioration within specific brain regions is considered as one of the principal bases for the development of major depressive disorders. Therefore, protects and promotes the maintaining of normal structure and function of neurons might be a potential therapeutic strategy in the treatment of depression. Here, we report that the antioxidant, N-acetylcysteine (NAC), inhibited neuronal injury through its capacity to reduce oxidative stress and exerted antidepressant effects. Specifically, we show that antioxidant enzyme activity was significantly decreased in the hippocampal CA1 region of depressive rats, while treatment with NAC (300 mg/kg, i.p.) produced neuroprotective effects against mitochondrial oxidative stress injuries and oxidative DNA damage in CA1 neurons of these rats. Moreover, NAC treatment alleviated neuronal injury resulting from neuroinflammation and apoptosis in depressed rats, effects that were associated with reductions in dendritic spine atrophy, and synapse deficits. These effects appear to involve a down-regulation of p38 mitogen-activated protein kinase (MAPK)-JNK signaling along with an up-regulation of ERK signaling within the hippocampal CA1 region. Moreover, this NAC treatment significantly ameliorated depression-like behaviors as indicated by performance in the sucrose preference and forced swim tests (FST). Taken together, these results reveal the potential involvement of oxidative stress in the generation of depression. And, the antidepressant-like effects exerted by NAC may involve reductions in this oxidative stress that can result in neuronal deterioration. Such neuroprotective effects of NAC may indicate a potential therapeutic strategy for the treatment of stress-related depression.

Neuroprotective effects of N-acetylcysteine via inhibition of matrix metalloproteinase in a mouse model of transient global cerebral ischemia

N-acetylcysteine (NAC) is known to serve many biological functions including acting as an antioxidant, and electing antiinflammatory effects. Previous reports have revealed that NAC may have neuroprotective effects against the deleterious effects of brain ischemia. Despite of this, the mechanism by which NAC prevents neuronal damage after brain ischemia remains unclear. The current study aimed to investigate this mechanism in a mouse model of transient global brain ischemia. In the present study, mice were subjected to 20 min of transient global brain ischemia, proceeded by intraperitoneal administration of NAC (150 mg/kg) in one group. The mice were then euthanized 72 h after this ischemic insult for collection of experimental tissues. The effect of NAC on neuronal damage and matrix metalloproteinase (MMP)-9 activity were assessed and immunofluorescence, and hippocampal terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay experiments were conducted and results compared between NAC- and vehicle-treated groups. Neuronal damage was primarily observed in the hippocampal CA1 and CA2 regions. In NAC-treated mice, neuronal damage was significantly reduced after ischemia when compared to vehicle-treated animals. NAC also inhibited increased MMP-9 activity after global brain ischemia. NAC increased laminin and NeuN expression and inhibited increases in TUNEL-positive cells, all in the hippocampus. These results suggest that NAC reduces hippocampal neuronal damage following transient global ischemia, potentially via reductions in MMP-9 activity.

Neuroprotective effect of N-acetylcysteine against cisplatin-induced toxicity in rat brain by modulation of oxidative stress and inflammation.

BackgroundNeurotoxicity is a major obstacle to the effectiveness of cisplatin (CDDP) in cancer chemotherapy. Oxidative stress and inflammation are considered to be the major mechanisms involved in CDDP-induced neurotoxicity. The rationale of our study was to investigate the efficacy of N-acetylcysteine (NAC) at two different doses in the management of CDDP-induced toxicity in rat brain by monitoring its antioxidant and anti-inflammatory effects.MethodsThirty-five male rats were divided into five groups (n=7) as follows: control group (0.5 mL saline), NAC100 group (100 mg/kg), CDDP group (8 mg/kg), NAC50-CDDP group (50 mg/kg NAC and 8 mg/kg CDDP), and NAC100-CDDP group (100 mg/kg NAC and 8 mg/kg CDDP). NAC was administered for 20 consecutive days, while CDDP was injected once on day 15 of the treatment protocol.ResultsThe neurotoxicity of CDDP was evidenced by a marked increase in acetylcholinesterase and monoamine oxidase activities. It also induced oxidative stress as indicated by increased levels of lipid peroxidation, nitric oxide, and protein carbonyl with a concomitant decline in reduced glutathione, glutathione peroxidase, glutathione S-transferase, superoxide dismutase, and catalase in the brain. Moreover, CDDP enhanced the synthesis of pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β, and interleukin-6. Treatment with NAC at the two selected doses significantly attenuated CDDP-induced changes in the brain cholinergic function, improved the brain oxidant/antioxidant status, and also reversed the overproduction of pro-inflammatory cytokines in brain and serum.ConclusionNAC could serve as an appropriate and safe complementary therapeutic agent to attenuate the toxicity of CDDP in the brain and therefore improve its outcomes in chemotherapy.

Neuroprotective effects of N-acetyl cysteine on primary hippocampus neurons against hydrogen peroxide-induced injury are mediated via inhibition of mitogen-activated protein kinases signal transduction and antioxidative action.

N-acetyl cysteine (NAC) has been extensively reported to exert neuroprotective effects on the central nervous system. Oxidative stress may contribute to the underlying mechanisms causing Alzheimer's disease (AD). The effect of NAC against oxidative stress injury was investigated in a cellular model of AD in the present study and the underlying mechanisms were revealed. The neuroprotective action of NAC (1, 10, 100 and 1,000µmol/l) on a cellular model of AD [hydrogen peroxide (H2O2)‑induced (3, 30 and 300µmol/l) toxicity in primary rat hippocampus neurons] demonstrated the underlying mechanisms. Cytotoxicity was measured using the MTT assay, and light microscopy and the dichloro-dihydro-fluorescein diacetate method were used to detect the reactive oxygen species (ROS) levels. Furthermore, the levels of mitogen-activated protein kinases (MAPKs) signal transduction and tau protein phosphorylation were measured via western blotting. NAC (100µmol/l) protected hippocampus neurons against H2O2‑mediated toxicity, as evidenced by enhanced cell viability. Using MTT assay and light microscopy for the observation of cell death, NAC ameliorated cell viability, which was induced by H2O2 injury (P<0.05). NAC was found to mitigate the excessive production of ROS (P<0.05). Another mechanism involved in the neuroprotective action of NAC may be its ability to inhibit MAPK signal transduction following H2O2 exposure. In addition, NAC may protect cells against H2O2‑induced toxicity by attenuating increased tau phosphorylation. Thus, the protective ability of NAC is hypothesized to result from inhibition of oxidative stress and downregulation of MAPK signal transduction and tau phosphorylation.

Effect of N‐Acetyl Cysteine against Aluminium‐induced Cognitive Dysfunction and Oxidative Damage in Rats

Aluminium is a potent neurotoxin involved in the initiation and progression of various cognitive disorders like Alzheimer's disease. Chronic aluminium exposure induces oxidative stress and increases amyloid beta levels in vivo. The role of oxidative stress has been well-suggested in these cognitive problems. Therefore, the present study was designed to explore the possible role of N-acetyl cysteine against aluminium mediating cognitive dysfunction and oxidative stress in rats. Aluminium chloride (100 mg/kg, p.o.) was given to rats daily for 6 weeks. N-acetyl cysteine (per se; 50 and 100 mg/kg, i.p.) pre-treatment was given 30 min. before aluminium daily for 6 weeks. On the third (21st day) and sixth week (42nd day) of the study, various behavioural tests (Morris water maze and elevated plus maze task paradigms) and locomotion (photoactometer) were done to evaluate cognitive tasks. The rats were killed on the 43rd day following the last behavioural test, and various biochemical tests were performed to assess the extent of oxidative damage. Chronic aluminium chloride administration resulted in poor retention of memory in Morris water maze, elevated plus maze task paradigms and caused marked oxidative damage. It also caused a significant increase in the acetylcholinesterase activity. Chronic administration of N-acetyl cysteine significantly improved memory retention in tasks, attenuated oxidative damage and acetylcholinesterase activity in aluminium-treated rats. The study suggests a neuroprotective effect of N-acetyl cysteine against aluminium-induced cognitive dysfunction and oxidative damage.

Antioxidant neuroprotection against ethanol-induced apoptosis in HN2-5 cells

Earlier studies from this and other laboratories show that ethanol induces apoptotic death of fetal and neonatal neurons. One mechanism that underlies these effects is the ethanol-associated reduction in the phosphatidylinositol 3′ kinase pro-survival pathway. Another mechanism involves the oxidative stress caused by the ethanol-associated increase in reactive oxygen species (ROS). In the present study, we used the murine HN2-5 hippocampal-derived cell line to investigate the effects of ethanol on ROS levels and apoptosis. We also investigated the potential neuroprotective effects of two structurally unrelated antioxidants: N-acetylcysteine (NAC) and melatonin. The results demonstrate that NAC blocked an ethanol-associated increase in ROS. In addition, NAC and melatonin prevented the augmentation of apoptosis in ethanol-treated neurons. Both antioxidants significantly elevated the expression of the anti-apoptotic gene XIAP in ethanol-treated and/or control neurons and melatonin increased Bcl-2 expression in ethanol-treated neurons. Thus, it is possible that the neuroprotective effects of NAC and melatonin involve their ability to augment the expression of one or more anti-apoptotic gene as well as their classical antioxidant actions. Additional studies are needed to establish the effectiveness of these antioxidants to prevent the loss of neurons which accompanies in utero exposure to ethanol.

N-acetylcysteine suppresses oxidative stress in experimental rats with subarachnoid hemorrhage

The neuroprotective effect of N-acetylcysteine (NAC), a sulfhydryl-containing antioxidant, on experimentally induced subarachnoid hemorrhage (SAH) in rats was assessed. NAC was administered to rats after the induction of SAH. Neurological deficits and brain edema were investigated. The activity of antioxidant defense enzymes, copper/zinc superoxide dismutase (CuZn-SOD) and glutathione peroxidase (GSH-Px), were measured in the brain cortex by spectrophotometer. The content of the lipid peroxidation product malondialdehyde (MDA) was also analyzed. We found that NAC markedly reversed the SAH-induced neurological deficit and brain edema. We further investigated the mechanism involved in the neuroprotective effects of NAC on rat brain tissue and found that NAC significantly increased CuZn-SOD and GSH-Px activity and decreased MDA content in the SAH brain. NAC has the potential to be a novel therapeutic strategy for the treatment of SAH, and its neuroprotective effect may be partly mediated via enhancing the activity of endogenous antioxidant enzymes and inhibiting free radical generation.

Neuroprotective effect of N-acetylcysteine in the development of diabetic encephalopathy in streptozotocin-induced diabetes

Diabetic encephalopathy is characterized by impaired cognitive functions that involve neuronal damage triggered by glucose driven oxidative stress. The objective of the present study was to determine whether N-acetylcysteine (NAC) supplementation ameliorates learning and memory deficits caused by hyperglycemia-induced oxidative stress in experimental diabetes. Male Wistar rats (200-250 g) were rendered diabetic by a single intraperitoneal injection of streptozotocin (50 mg/kg). Cognitive deficits were observed in diabetic animals assessed using elevated plus maze test after 8 weeks of induction of diabetes. Acetylcholinesterase activity, a marker of cholinergic function, was decreased by 15.6% in the cerebral cortex, 20.9% in cerebellum and 14.9% in brain stem of diabetic rats compared to control rats. There was an increase in lipid peroxidation in cerebral cortex (21.97%), cerebellum (20.4%) and brain stem (25.5%) of diabetic rats. This was accompanied by decrease in glutathione and total thiol content along with decrease in the activities of superoxide dismutase, catalase and glutathione reductase. However, glutathione peroxidase activity increased by 11.2%, 13.6% and 23.1% in cerebral cortex, cerebellum and brain stem respectively, while the activity of glutathione-s-transferase decreased only in cerebral cortex (21.7%). Supplementation with NAC (1.4 g/kg/day in drinking water) significantly attenuated cognitive deficits and oxidative stress in diabetic rats. Our results emphasize the involvement of increased oxidative stress in cognitive impairment in diabetic animals and point towards the potential beneficial role of NAC as an adjuvant therapy to conventional anti-hyperglycemic regimens for the prevention and treatment of diabetic encephalopathy.

N‐acetylcysteine prevents β‐amyloid toxicity by a stimulatory effect on p35/cyclin‐dependent kinase 5 activity in cultured cortical neurons

Although previous studies have indicated that the neuroprotective effect of N-acetylcysteine (NAC) required activation of the Ras-extracellular-signal-regulated kinase (ERK) pathway, the detailed mechanisms and signal cascades leading to activation ERK are not clear. In the present study, we investigated the effect of NAC on A beta(25-35)-induced neuronal death. Pretreatment of neurons with NAC 1 hr before application of A beta prevented A beta-mediated cell death. NAC increased cyclin-dependent kinase 5 (Cdk5) phosphorylation, an effect that was blocked by Cdk5 inhibitor. The neuroprotective effect of NAC was significantly attenuated by Cdk5 inhibitors or in neurons transfected with Cdk5 or p35 small interfering RNA (siRNA). Conversely, pretreatment of neurons with the calpain inhibitors calpeptin or MDL28170 enhanced the neuroprotective effect of NAC. A beta(25-35) caused a significant decrease in the level of p35, with a concomitant increase in p25, which was completely prevented by NAC. This effect of NAC was blocked by the Cdk5 inhibitors roscovitine and butyrolactone. In addition, NAC increased Cdk5/p35 kinase activity but reduced Cdk5 kinase activity. A beta(25-35) treatment decreased phosphorylated levels of ERK, which could be reversed by NAC. The effect of NAC was completely blocked by Cdk5 inhibitors. NAC reversed the A beta(25-35)-induced decrease in the expression of Bcl-2, which could be blocked by the MAPK kinase (MEK) inhibitor or Cdk5 inhibitors. These results suggest that NAC-mediated neuroprotection against A beta toxicity is likely mediated by the p35/Cdk5-ERKs-Bcl-2 signal pathway.

Antioxidative and anti-inflammatory effects of four cysteine-containing agents in striatum of MPTP-treated mice

Objectives Mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were used to examine the neuroprotective effects of n-acetyl cysteine (NAC), s-ethyl cysteine (SEC), s-methyl cysteine (SMC), and s-propyl cysteine (SPC). Methods Each agent at 1 g/L was directly added to the drinking water for 3 wk. Mice were treated by subcutaneous injection of MPTP (24 mg/kg body weight) for 6 consecutive days. The brain from each mouse was quickly removed and the striatum was collected for analyses. Results The MPTP treatment significantly depleted striatal glutathione content, reduced the activity of glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase, increased malondialdehyde level, and elevated interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels in striatum ( P < 0.05). The pre-intake of NAC, SEC, SMC, and SPC significantly attenuated MPTP-induced glutathione loss, retained the activity of GPX and SOD, diminished oxidative stress, and suppressed MPTP-induced elevation of IL-6 and TNF-α ( P < 0.05). MPTP treatment significantly suppressed GPX mRNA expression and enhanced TNF-α mRNA expression ( P < 0.05). Compared with MPTP treatment alone, the pre-intake of NAC, SEC, SMC, and SPC significantly elevated GPX mRNA expression and diminished TNF-α mRNA expression ( P < 0.05), in which SPC showed the greatest suppressive effect against MPTP-induced TNF-α mRNA expression ( P < 0.05). Dopamine and 3,4-dihydroxyphenylacetic acid contents in the striatum were significantly decreased by MPTP treatment ( P < 0.05). The pre-intake of four test agents significantly improved MPTP-induced dopamine depletion and increased dopamine/3,4-dihydroxyphenylacetic acid content ( P < 0.05). Conclusion These results suggest that these cysteine-containing compounds could provide antioxidative and anti-inflammatory protection for the striatum against the development of Parkinson’s disease.

Neuroprotective Effects of N-acetylcysteine on Experimental Closed Head Trauma in Rats

N-acetylcysteine (NAC) is a precursor of glutathione, a potent antioxidant, and a free radical scavenger. The beneficial effect of NAC on nervous system ischemia and ischemia/reperfusion models has been well documented. However, the effect of NAC on nervous system trauma remains less understood. Therefore, we aimed to investigate the therapeutic efficacy of NAC with an experimental closed head trauma model in rats. Thirty-six adult male Sprague-Dawley rats were randomly divided into three groups of 12 rats each: Group I (control), Group II (trauma-alone), and Group III (trauma+NAC treatment). In Groups II and III, a cranial impact was delivered to the skull from a height of 7 cm at a point just in front of the coronal suture and over the right hemisphere. Rats were sacrificed at 2 h (Subgroups I-A, II-A, and III-A) and 12 h (Subgroups I-B, II-B, and III-B) after the onset of injury. Brain tissues were removed for biochemical and histopathological investigation. The closed head trauma significantly increased tissue malondialdehyde (MDA) levels (P < 0.05), and significantly decreased tissue superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities (P < 0.05), but not tissue catalase (CAT) activity, when compared with controls. The administration of a single dose of NAC (150 mg/kg) 15 min after the trauma has shown protective effect via decreasing significantly the elevated MDA levels (P < 0.05) and also significantly (P < 0.05) increasing the reduced antioxidant enzyme (SOD and GPx) activities, except CAT activity. In the trauma-alone group, the neurons became extensively dark and degenerated into picnotic nuclei. The morphology of neurons in the NAC treatment group was well protected. The number of neurons in the trauma-alone group was significantly less than that of both the control and trauma+NAC treatment groups. In conclusion, the NAC treatment might be beneficial in preventing trauma-induced oxidative brain tissue damage, thus showing potential for clinical implications.

Neuroprotective effect of N-acetyl cysteine on hypoxia-induced oxidative stress in primary hippocampal culture

Hippocampus has received a considerable attention in the recent past due to its role in a number of important functions such as learning and memory. The effect of hypoxia on neuronal cell injury especially on hippocampal cells is not well known. The aim of the present study was to characterize the biochemical changes in primary cultured hippocampal neurons during hypoxic exposure and the protective effect of N-acetyl cysteine on hypoxia-induced cytotoxicity. The hippocampal culture grown in 24-well plates was exposed to hypoxia for 3 h in a dessicator in 95% N 2, 5% CO 2 atmosphere at 37 °C. Later, the cells were allowed to recover for 1 h under normoxia. It was observed that there is an appreciable increase in cytotoxicity in cells exposed to hypoxia. Further, there was a significant decrease in mitochondrial membrane potential and appreciable increase in reactive oxygen species and single-strand DNA breaks in cells exposed to hypoxia compared to control. There is a significant fall in glutathione peroxidase, glutathione reductase, reduced glutathione levels, and nitric oxide in the cells exposed to hypoxia. Significant elevation in the intracellular calcium level in the cells on exposure to hypoxia was observed. Supplementation with NAC (50 μM) resulted in a significant cytoprotection, fall in ROS generation, and higher antioxidant levels similar to that of control cells. NAC also inhibited DNA strand breaks induced by hypoxia. The study indicates that NAC has significant neuroprotective activity during hypoxia in primary hippocampal culture.

Neuroprotective effect of N-acetylcysteine and hypothermia on the spinal cord ischemia–reperfusion injury

The purpose of this study was to investigate the effect of N-acetylcysteine (NAC) on spinal cord ischemia–reperfusion (I–R) in rabbits. Thirty rabbits were divided into five equal groups, group I (sham-operated, no I–R), group II (control, only I–R), group III (I–R+NAC), group IV (I–R+hypothermia), group V (I–R+NAC+hypothermia). Spinal cord ischemia was induced by clamping the aorta both below the left renal artery and above the aortic bifurcation. Forty-eight hours postoperatively, the motor function of the lower limbs was evaluated in each animal according to Tarlov Score. Spinal cord samples were taken to evaluate the histopathological changes. The sham-operated rabbits (group I) showed no neurologic deficit (Score=4). Paraplegia (Score=0) developed in all rabbits in the control group (group II). Administration of 50 mg/kg of NAC (group III) resulted in significant reduction of motor dysfunction (Score=3.1±1.3, p=0.002). Application of hypothermia alone (group IV) showed significant recovery of motor functions (Score=3.0±1.1, p=0.002), and combination of hypothermia and 50 mg/kg of NAC (group V) showed complete recovery of lower limb motor function (Score=4, p=0.001). Histologic examination of the spinal cord in rabbits with paraplegia revealed several injured neurons. The cords of animals with no motor function deficits showed only minimal cellular infiltrates in the gray matter, and there was good preservation of nerve cells. NAC showed protective effects of the spinal cord. Moderate hypothermia alone also showed protective effects. Combined use of NAC and hypothermia resulted in highly significant recovery of spinal cord function.