NEUROPROTECTIVE POTENTIAL OF CINNAMON: EVIDENCE FROM ANIMAL MODELS, MECHANISTIC INSIGHTS, AND THERAPEUTIC IMPLICATIONS

NEUROPROTECTIVE POTENTIAL OF CINNAMON: EVIDENCE FROM ANIMAL MODELS, MECHANISTIC INSIGHTS, AND THERAPEUTIC IMPLICATIONS

Vismaya *, P. S. Rajini and M. Muralidhara

Department of Biochemistry, Bangalore City University, Central College Campus, Bangalore, Karnataka, India.

ABSTRACT: Owing to the abundant evidence in preclinical models, Cinnamon, and its bioactive constituents are being explored currently for their preventative and therapeutic potential against select neurodegenerative conditions. Cinnamon contains a wide variety of bioactive components viz., cinnamaldehyde, eugenol, cinnamic acid, tannin, catechin, proanthocyanidin, monoterpenes, sesquiterpenes, and coumarin. Cinnamon bark powder, its various extracts and selected components have shown promising results in numerous in-vitro and in-vivo preclinical models. Its efficacy as an antioxidant, anti-inflammatory, and cognitive enhancing properties, and its propensity to modulate several key biochemical and molecular targets in AD, PD, and TBI models has raised considerable interest among researchers who strongly advocate the use of natural compounds to delay /prevent the progression of neurodegenerative conditions. The present review aims to discuss the status of the current data related to the therapeutic propensity of Cinnamon and its derivatives and highlights the need for well-designed clinical trials.

Keywords: Cinnamon, Bioactives, Neuromodulation, Neuroprotection, In-vitro, In-vivo models, Clinical evidence

INTRODUCTION: About 250 species of cinnamon have been identified within the genus (Cinnamomum spp.), which is a perennial tree of tropical medicine and a member of the Lauraceae family ^{1, 2}. The Arabic and Hebraic word ‘amomon’ is the source of the botanical name ‘cinnamomum’, which means "fragrant spice plant." However, the Greek term ‘kinamon’, which means "Arabian spice," is the source of the popular name cinnamon ³. Only two of the 250 species of the genus Cinnamomum Cinnamomum verum, formerly known as Cinnamomum zeylanicum, and Cinnamomum cassia are widely distributed.

Since ancient times, cinnamon, a tree of intermediate height (10 to 15 meters), has been utilized as a spice plant in traditional medicine and food preparation all across the world ⁴. Common uses for cinnamon include oleoresin, bark sticks, bark powder, bark essential oil, and leaf essential oil. The essential oil of cinnamon has a sweet, spicy, slightly woody, clove-like perfume, and the aroma is highly distinctive ⁵. The flavor of cinnamon is warm, spicy, and aromatic. Because of its scent, which can be added to various meals and perfumes, cinnamon is mostly employed in the aroma and essence industries ⁶.

A wide spectrum of pharmacological effects of cinnamon is widely documented. It contains several polyphenols and bioactive substances like eugenol and cinnamon aldehyde. Numerous Pharma-cological qualities, including anti-inflammatory, anti-diabetic, anti-microbial, and antioxidant ones, are said to be present. It has been praised as a powerful intervention spice in lowering the risk of several chronic diseases because of these qualities ⁷. The anti-inflammatory properties of cinnamon may also help with diseases like multiple sclerosis and aging-related cognitive loss ⁸. Numerous preclinical study findings have drawn significant attention in recent decades due to their potential therapeutic application in the treatment of many neurodegenerative disorders, including Parkinson's disease (PD) and Alzheimer's disease (AD) ^{9, 10}.  Cinnamon's bioactive components have been shown to decrease oxidative brain damage, lower neuroinflammation, and alter neurotransmitter activity. Curiously, studies have demonstrated that cinnamon protects against neurotoxicity, increases synaptic plasticity, and improves cognitive performance ¹¹. Due to the growing body of data in preclinical models indicating cinnamon and its bioactives have important neuroprotective benefits, numerous researchers are investigating their potential as a treatment for specific neurodegenerative diseases. The evidence that cinnamon and its bioactive compounds have a broad range of neuroprotective potential in different disease models, as well as their likely method of action and prospective future research directions, is the main focus of this review.

Major Bioactive Molecules, Structure: Cinnamon contains various bioactive compounds that have numerous pharmacological properties. It consists of a variety of resinous compounds, including cinnamaldehyde (CA), trans-cinnamaldehyde (TCA), cinnamic acid, and numerous essential oils ¹². A wide range of components in cinnamon essential oils includes CA, Eugenol, Cinnamyl acetate, Linalool, Cinnamic acid, Benzyl benzoate, Coumarin, vanillin, Camphor, etc ^{13, 7}. The major constituents of cinnamon bark oil reported are: Trans-cinnmaldehyde (TCA 91.56%); Cinnamylacetate (1.72%); Eucalyptol (1.26%); Cis cinnamaldehyde (1.28%); Coumarin (0/72%); α-Muurolene (0.72); and α-Cubebene (0.46%). The bioactive chemicals in cinnamon have been separated using a variety of techniques, and the conventional ways of extracting essential oils include steam distillation, hydro distillation, and organic solvent extraction ¹⁴. Although the majority of techniques use solvents like methanol, ethanol, and chloroform ¹⁵, new extraction techniques have recently been created using supercritical fluid with the use of microwaves or ultrasounds ¹⁶.

Water extraction, however, is the most accessible and safest approach for human health. Using ultra-performance liquid chromatography–high-resolution mass spectrometry (UPLC–HRMS) to profile aqueous cinnamon extract has verified the presence of chemicals such rosavin, camphor, and L (−)-carnitine ¹⁷. Eight ketones, seven monoterpene hydrocarbons, thirty oxidized monoterpenes, four sesquiterpene hydrocarbons, and twenty-three oxidized sesquiterpene hydrocarbons are among these substances ¹⁸. The chemical structures of some important constituents of cinnamon are presented in Fig. 1.

FIG. 1: CINNAMON AND ITS SELECTED BIOACTIVE COMPONENTS

Neuroprotective Propensity of Cinnamon -Multiple Pharmacological Properties: Abundant preclinical evidence has demonstrated the neuroprotective activities of Cinnamon bark and its extracts and major bioactive components in various preclinical models.

Pharmacological Attributes Responsible for Neuroprotection: Cinnamon and its bioactive compounds can exert their potential neuroprotective effects via different mechanisms. Three major mechanisms, viz., antioxidant, anticholinergic and anti-inflammatory, have been largely explored with cinnamon and bio-actives in various preclinical paradigms. A few salient findings in cell models have been presented in Table 1.

TABLE 1: MAJOR EVIDENCE OF NEUROMODULATION IN CELL MODELS

Antioxidant and Anticholinergic Attributes: Currently, spices and medicinal plants have received wide attention as sources of beneficial antioxidants against various diseases, including neurodegenerative disorders ¹⁹. Cinnamon is a potent antioxidant, anticholinergic, and antidiabetic due to its high phenolic content ²⁰. In a comparative study among 26 spices, cinnamon showed the highest antioxidant activity ²¹ and its antioxidant potential  have been attributed to the presence of various constituents viz., pyrogallol, ferulic acid, and p-coumaric acid in along with p-hydroxybenzoic acid, p-coumaric acid, and pyrogallol in the ethanolic and aqueous extracts. Flavonoids from cinnamon have demonstrated notable antioxidant and free-radical-scavenging capabilities ²².

Repeated oral administration (90 d) of the bark powder of C. verum (10%) produced antioxidant activities as indicated by cardiac and hepatic antioxidant enzymes, lipid conjugate dienes, and glutathione ²³. CA and other cinnamon components also have significant inhibitory effects on the expression of inducible nitric oxide (NO) and nitric oxide production ⁷. Additionally, the suppression of pyrogallol autoxidation demonstrated that cinnamon oil had superoxide dismutase (SOD)-like action ²⁴. Remarkably, when compared to the natural antioxidant 𝛼-tocopherol, both ethanolic and hot water extracts of the dry bark of C. cassia demonstrated greater antioxidant activity in-vivo ²⁵. Cinnamon is extensively studied for its anti-cholinesterase (AChE) activity. The essential oil (EO) of Cinnamomum verum demonstrated antioxidant activity, as evidenced by its ability to scavenge free radicals as well as reduce ferric ions ²⁶. Employing an in-silico approach, Syarafina et al., ²⁷ screened 60 bioactive compounds from cinnamon bark to identify potential AChE inhibitors. 12 out of 15 tested ligands showed potential as AChE inhibitors, with epicatechin and medioresinol demonstrating the highest affinity, comparable to the natural ligand donepezil. Another study ²⁸ also demonstrated that cinnamon EO) exhibited good inhibitory activity against both AChE and butyrylcholinesterase (BChE), and also against BACE1 enzyme, a key enzyme in the production of amyloid-beta, a protein that forms plaques in the brains of AD patients. Molecular docking simulations have also suggested that compounds such as Coumarin, Piperonal, Cinnamaldehyde dimethyl, and alpha-Copaene could potentially inhibit human AChE.

Anti-inflammatory Effects: Cinnamon constituents are known to inhibit neuro-inflammation as evidenced by both in-vitro and in-vivo studies. Predominantly, these actions are mediated by the antioxidant and free radical scavenging activities of cinnamon constituents. CA is the most effective anti-neuroinflammatory compound in cinnamon extract ²⁹.

In neurodegenerative conditions like AD and PD, microglial activation contributes to neuro-inflammation and neuronal death. If neuro-inflammation is managed, outcomes of neurodegenerative diseases may be improved. In lipopolysaccride-activated BV2 microglia, cinnamon extract dramatically reduced the synthesis and expression of NO, interleukin (IL)-1b, IL-6, and tumour necrosis factor (TNF)-α and Cinnamon’s ability to reduce neuroinflammation most likely resulted from blocking the activation of nuclear factor-kB. By inhibiting the nuclear factor kappa B (NF-κB) signaling pathway and reducing neuroinflammation, both TCA and HCA significantly reduced LPS-induced neuronal mortality in-vitro ³⁰. HCA also inhibited neuroinflammatory signaling pathways by targeting low-density lipoprotein receptor-related protein 1 (LRP1), which in turn inhibited NF-κB, extracellular regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p-38 MAPK) ³¹.

In mice models, TCA was shown to reduce the selective dopaminergic neuronal death that occurred in the Substantia nigra of 1,1,1,2-,3,6,- tetrahydropyridine (MPTP) mice models as evidenced by the attenuation of the MPTP-mediated stimulation of LC3 puncta, a microtubule-associated protein. In the same model, CA treatment increased downregulated p62 in the Substantia nigra of MPTP mice. These findings suggest that CA has neuroprotective effects in PD models ³². Further, Cinnamic aldehyde blocks the autophagy of the neuronal cells from the toxic effect of 1-methyl-4-phenyl-1,2,3,6- tetrahydro-pyridine by stopping the stimulation pf microtubule associated protein light chain 3 (LC3) and enhanced the down regulation of p62 there by blocking the autophagy inhibitors in PD models ³³.

Numerous researchers have explored the anti-inflammatory potential of TCA. TCA markedly reduced inflammation in microglia, neural damage, apoptosis, myelin degeneration ^{30, 29, 34}, dysfunctional protein aggregation, and overall function of the nervous system ^{35, 11}. In mice with neuroinflammation, TCA reduced memory impairment via reducing microglial activation by disrupting NO synthase mRNA ³⁶. It dramatically decreased the production of NO and ROS ³⁷. TCA therapy restored tau-protein hyperphosphorylation and aberrant synaptic protein expression in the hippocampus and prefrontal cortex of PS cDKO double knockout mice. Importantly, TCA’s interrupting effect NFκB signaling pathway resulted in the regulation of neuroinflammatory responses, which improved NMDA receptor dysfunction and memory deficits in PS cDKO mice ³⁸.

The neuroprotective effects of Cinnamon bio-actives were also studied in traumatic brain injury (TBI) models. TBI can seriously impair brain function and cause several ischemic pathologic changes in the brain. CA demonstrated neuroprotective effects by limiting neutrophil recruitment, lowering ROS levels, minimizing histologic damage, and alleviating acute hippocampal dysfunction ³⁹. Interestingly, administering cinnamon polyphenol extract has also demonstrated notable neuroprotective effects in TBI situations ⁴⁰. Malondialdehyde, superoxide dismutase, glutathione peroxidase, and other oxidative parameters, as well as inflammatory markers like NF-kB, interleukin 1-beta, interleukin 6, nuclear factor erythroid 2-related factor 2, glial fibrillary acidic protein, and neural cell adhesion molecule, were all significantly altered in this model. The extract also significantly reduced the formation of infarct and edema in this model. Many substances present in cinnamon essential oil, including as TCA, caryophyllene oxide, eugenol, and cinnamonyl acetate, demonstrated exceptional anti-inflammatory qualities by lowering the production of NO by macrophages stimulated by lipopolysaccharide. Additionally, several other pieces of evidence in animal disease models suggest its usage as a safe preventive and therapeutic agent against neurological illnesses such migraine, attention deficit hyperactivity disorder, AD, PD and neuroinflammation.

Antidepressant Potential of Cinnamon: The efficacy of cinnamon bark, different extracts, and cinnamon oil to mitigate depression associated biochemical processes has been well demonstrated. Phenols generated from cinnamon can counteract oxidants that result in oxidative stress, which lowers the incidence of inflammatory activity in brain neuron cells. A recent study found that the phenols in cinnamon extract effectively reduced the action of TNF-α, a pro-inflammatory cytokine, in the hippocampus and neuron cells, restoring optimum and elevating serotonin levels in the brain ⁴¹. In the past, it was demonstrated that sodium benzoate, a metabolite of cinnamonaldehyde, increased BDNF activity, which is involved in the stimulation of dopamine receptor expression ⁴². Further, mice treated with a hydroalcoholic extract of cinnamon (C. verum) showed significant anti-depressant and anti-anxiety benefits in a lead acetate paradigm ⁴³.

Using various behavioral tests, a recent study showed how inhaling cinnamon essential oil (CIEO) affected mice behavior ⁴⁴. Anxiolytic effects and improved social conduct were demonstrated by CIEO inhalation. Microarray investigation of the hippocampus after CIEO therapy showed overexpression (15 genes) and downregulation (17 genes). Interestingly, the most important genes among them that are engaged in biological pathways and processes connected to anxiety, such as the control of neuroinflammation and neuronal death, are Dcc, Egr 2, and Fos. Similarly, it was demonstrated that cinnamal-dehyde, the primary ingredient in CIEO, significantly improved the recovery of MK-801-induced anxiety-related alterations in a zebrafish model, as demonstrated by the electro-encephalogram power spectrum.

In mouse models, a standardized methanolic extract of C. cassia bark was evaluated for antidepressant activity using various behavioral tests such as the tail suspension test (TST), forced swim test (FST), and locomotor activity test. The C. cassia extract significantly decreased the immobility time in TST, increased 5-hydroxytryptophan (5-HTP) -induced tremors that led the authors to speculate that the serotonergic system is most likely involved ⁴⁵. Similar studies with aqueous extract of cinnamon (C. verum) bark showed an antidepressant-like effect among mice exposed to open-space forced swim test (OSFST), and failed to significantly affect non-spatial short-term memory and locomotor activity of the mice subjected to NORT (Novel Object Recognition Test) and OFT (Open Field Test), respectively ⁴⁶. Intraperitoneal administration of cinnamon essential oil significantly decreased the immobility time of both FST and TST as compared to the control group of mice ⁴⁷. Based on these results, the researchers attributed this potential to trans-cinnamaldehyde, and suggested that cinnamon essential oil may serve as an adjunctive therapy in improving symptoms of depressive and anxiety disorders.

In rat models of depression, few studies have also documented the antidepressant efficacy of Cinnamon (C. burmannii) bark extract (CE) employing chronic mild stress induced (CMS) models ⁴⁸. Study showed that CE could reduce the immobility when compared to the CMS group. Interestingly, improved serotonin levels in the hippocampus were accompanied with increased expression of TNF-α expression as a marker of inflammation had increased in the CMS group. Another study, showed that hydroalcoholic extract of Cinnamon (HEC) significantly attenuated the immobility time, was significantly increased in the depressed group ⁴⁹. Interestingly, an increase in the BDNF protein and TrkB gene expression levels were also evident in the prefrontal cortex of the treatment groups.

The potential of CA to influence the intergenerational inheritance of depression in mice models of depression generated by chronic moderate stress (CMS) and paternal stress exposure-induced elevated corticosterone (CORT) ⁵⁰. According to this study, co-administration of CA to F0 males protected the F1 male offspring from exhibiting depressive-like traits. Additionally, CA dramatically improved the depressive-like behaviors of F1 offspring born to CMS mice that were triggered by chronic variable stress (CVS). Increased miR-190b expression was associated with decreased BDNF and GR in the hippocampus of F1 males of CORT-or CMS-induced depressive-like animals; these effects were mitigated by CA. In an interesting approach, a recent investigation explored the effects and mechanisms of Cinnamon Oil Solid Self-Micro emulsifying Drug Delivery System (CO-S-SME) in a chronic unpredictable mild stress (CUMS)-induced mouse model (51). According to behavioral tests, CO-S-SME may successfully alleviate depressive-like behaviors in CUMS mice, as demonstrated by elevated neurotransmitter levels and decreased corticosteroid and inflammatory factor expressions. Based on these findings, CO-S-SME may be an effective antidepressant that acts through CORT, inflammatory cytokines, and monoamine neurotransmitters. (Please refer Table 3B).

Cognitive Enhancing Potential of Cinnamon: Evidence gathered both in-vitro and in-vivo has demonstrated the cognitive enhancing potential of cinnamon and its components as reviewed recently ⁸. Several in-vitro studies have reported a positive impact on cognitive function in models. A methanol extract of cinnamon bark inhibited Aβ40 production in APP-CHO cells ⁵², while cinnamaldehyde inhibited Aβ aggregation and increased cell viability in APP (amyloid precursor protein) and APPsw cell lines ⁵³. Studies reported that trans-cinnamaldehyde reduced neural death in microglial and neuronal cell lines ³⁰, and cinnamaldehyde significantly reversed Aβ neurotoxicity in SH-SY5Y neuroblastoma cells ⁵⁴ (refer to Tables 2 and 4A).

Following the injection of cinnamon components, multiple in-vivo studies have also demonstrated considerable beneficial outcomes revealing the cognitive benefits, which are consistent with various in-vitro findings. Nevertheless, the discrepancies found in these investigations can be attributed to changes in the types of behavioral tests performed, the routes and durations taken, and quantities of cinnamon components supplied. Additionally, because of its general activities as an antioxidant, an inhibitor of amyloid plaque, and an anti-acetylcholinesterase, eugenol has cognitive protective properties. There is evidence that both CA and TCA enhance insulin and NO signaling and provide protection against cognitive decline.

A controlled cortical impact (CCI)-induced preclinical mouse model of traumatic brain injury (TBI) was used to test NaB to investigate the potential therapeutic effectiveness of cinnamon metabolite ⁵⁵. It has been demonstrated that oral administration of NaB reduces microglia and astrocyte activation and inhibits the production of inducible iNOS in the cortex and hippocampal regions of mice exposed to CCI. Additionally, NaB lowered the size of the lesion cavity and vascular damage in the brain among mice with CCI. Mice treated with NaB exhibited a significant decrease in depressive-like behaviors as well as notable improvements in memory and locomotor abilities. Likewise, in rats with TBI, phosphate buffer extract (CE) of cinnamon bark virtually eliminated memory loss and reduced neuronal loss ⁵⁶. There were no appreciable variations in anxiety or motor activity, and CE consumption reduced neuronal loss in the dentate gyrus and temporal cortex. These results have demonstrated a novel therapy strategy to enhance cognitive performance and lessen memory loss in TBI patients.

Preclinical Evidence in Animal Models: 

Evidence in Invertebrate Models: Studies of cinnamon constituents on neuromodulatory potential in invertebrate models have been very promising Table 2.

TABLE 2: NEUROMODULATORY EFFECTS OF CINNAMALDEHYDE, CINNAMON EXTRACT IN INVERTEBRATE MODELS

CA improved the lifespan of both AD and non-AD Drosophila and enhanced the health span of Tau-overexpressing AD flies ⁵⁷. Cinnamon extract significantly improved behavioral symptoms and α-synuclein aggregation in a Drosophila model of PD ⁵⁸. ACE cinnamon extract protected Drosophila against rotenone-induced mortality, locomotor deficits, and oxidative damage while restoring mitochondrial function ⁵⁹. Cinnamon bioactive compounds ameliorated neurodegeneration and neurotoxicity markers in C. elegans ⁶⁰. In C. elegans, cinnamaldehyde reduced β-amyloid toxicity via mTORC1 and autophagy signaling, promoting longevity ⁶¹.

TABLE 3A:  NEUROMODULATORY EFFECTS OF CINNAMON, CINNAMON OIL, AND SODIUM BENZOATE

TABLE 3B: EXPERIMENTAL MODELS (IN-VIVO) WHICH DEMONSTRATE THE NEURO PROTECTIVE EFFICACY OF CINNAMALDEHYDE (CA)

Evidence in In-vivo Disease Models: Salient findings documented in various in-vivo models have been summarized in Tables 4A & B; likewise, selected data on the different extracts of cinnamon are presented in Table 5.

TABLE 4A: MAJOR IN-VIVO STUDIES DESCRIBING THE NEUROMODULATORY EFFECTS OF TRANS- CINNAMALDEHYDE (TCA)

TABLE 4B: IN-VIVO STUDIES WITH EUGENOL AND CINNAMIC ACID

TABLE 5: IN-VIVO STUDIES WITH CINNAMON EXTRACTS

PD and AD Models: Several investigations have shown that cinnamon extracts and NaB have neuro-modulatory actions, which amply support their positive benefits in AD and PD models. It has been found that NaB modulates mevalonate metabolites to upregulate DJ-1(9). In the mouse central nervous system, cinnamon extracts and NaB also increase neurotrophin-3 (NT-3) and neurotropic factors such BDNF ⁴². A naturally occurring substance called "CEppt," which was separated from cinnamon extract, dramatically decreased the production of harmful ΝA𝛽-amyloid polypeptide (A𝛽) oligomers and prevented their toxicity to neuronal PC12 cells. According to the study, CEppt completely eliminated the tetrameric species of A𝛽 in the brain of the fly model of AD, resolved the reduced immovability, and improved the locomotion deficiencies. This resulted in a discernible decrease in A𝛽 oligomers, which in turn reduced plaques and enhanced the cognitive function of transgenic mouse models ⁶². Two of the primary characteristics of AD, tau aggregation and filament development, may be lessened by the aqueous extract of C. zeylanicum, according to another study. Cinnamon may be used to treat AD since the extract may promote the full fragmentation of recombinant tau filaments and significantly alter the form of paired helical filaments from AD brain ⁶³.

It is generally known that neurotrophic factors, a family of chemicals, maintain the survival of existing neurons while also stimulating and regulating neurogenesis. In-vivo, studies have demonstrated that oral administration of ground cinnamon increased BDNF and NT-3 levels in the mouse central nervous system ⁴².  The expression of BDNF and NT-3 in primary human neurons and astrocytes was also dose-dependently increased by NaB. Its neurotrophic effect through CREB activation was evident from the recruitment of CREB and CREB-binding protein to the BDNF promoter by NaB, the siRNA knockdown of CREB, and the further activation of cAMP Response element binding (CREB) protein ⁴².

In AD models, TCA reduced amyloid-β deposition by regulating BACE1 through the SIRT1-PGC1α-PPARγ pathway in 5XFAD mice ⁶⁴. It also restored NMDA receptor function and memory in PS cDKO mice via NF-κB suppression ³⁸ and protected against aluminum-induced AD-like changes in rats ⁶⁵. Additionally, TCA exhibited antidepressant effects in mice by modulating serotonin levels and neurotransmitter balance ⁶⁶.

TBI Model: In a rat TBI model, CA reduced neutrophil infiltration, suppressed ROS, and minimized hippocampal dysfunction ³⁹. In memory impairment model, CA improved cognitive function through the ERK pathway by decreasing ERK1/2 phosphorylation in the prefrontal cortex ⁶⁷. In addition, CA enhanced sciatic nerve recovery after crush injury by improving the sciatic functional index, muscle mass ratio, and myelin content, suggesting its role in nerve regeneration ⁶⁸. In mice, CA exhibited a biphasic effect on passive avoidance memory, enhancing memory at doses of 45–100 mg/kg while impairing it at lower doses ⁶⁹. In mice models, TCA improved memory by upregulating antioxidant enzymes, activating the Nrf2 pathway, and inhibiting oxidative stress factors (IL-1β, MDA, caspase-3), thereby preventing Aβ1-42 aggregation ⁷⁰. In C57BL/6 mice, TCA reduced neuroinflammation by downregulating iNOS and COX-2 while mitigating LPS-induced changes in BV-2 microglial cells ³².

Eugenol improved memory impairments in rats by counteracting the detrimental effects of lead acetate exposure ⁷¹. Data on Eugenol and its protective effects is presented in Table 4 d. In AD model, it enhanced cognition by reducing amyloid plaque deposition, as confirmed by histological and behavioral studies ⁷². Moreover, Eugenol promoted neurogenesis and memory performance in mice by increasing neural stem cells in the dentate gyrus while reducing neuronal cell death ⁷³. Trans-cinnamic acid showed neuroprotective effects in 5XFAD transgenic mice by inducing lysosomal biogenesis through TFEB upregulation. This led to a remarkable reduction in cerebral amyloid-beta plaque burden and improved spatial memory ⁷⁴.

Cinnamon Extracts: In a trauma model (mice), cinnamon improved cognition and traumatic brain injury symptoms ⁴⁰ Table 5. In multiple sclerosis (MS) models, cinnamon ingestion alleviated symptoms of both acute and chronic experimental autoimmune encephalomyelitis (EAE), preserved blood-brain barrier, reduced neuroinflammation and demyelination ³⁴.

Cinnamon essential oil exhibited antidepressant and anxiolytic properties ⁴⁷. Moreover, cinnamon oil-based self-microemulsifying drug delivery system (CO-S-SME) improved depression-like behaviors in mice subjected to chronic unpredictable mild stress (CUMS). It increased neurotransmitter levels, reduced corticosterone and inflammatory factors, and positively altered gut microbiota composition ⁵¹.

As presented in Table 5, aqueous cinnamon extract (ACE) has shown neuroprotective effects in various cognition-related models. In diabetic rats, ACE enhanced spatial and avoidance memory, indicating cognitive benefits ⁷⁵. In an aluminum-induced AD rat model, ACE improved memory and intellectual performance while preventing amyloid-beta formation ⁶⁵. Consistent with this data, in TBI mice, ACE significantly mitigated memory impairment, preserved neuronal integrity in the temporal cortex and dentate gyrus, and improved cognitive functions ⁵⁶. In PD model, ACE and cinnamaldehyde enhanced motor function in MPTP-lesioned mice and protected dopaminergic neurons in the substantia nigra ⁷⁶. Also, in AD rat model, ACE improved insulin sensitivity, inhibited cholinesterase activity, and enhanced neuronal survival in the hippocampus ⁷⁷.

Cinnamon polyphenol extract reduced post-traumatic edema and infarct in C57BL/6 mice with traumatic brain injury (TBI), by modulating oxidative stress and inflammatory markers ⁴⁰. In AD models, cinnamon extract (CE) alleviated cognitive impairment in STZ-diabetic rats and enhanced cognitive function in formaldehyde-exposed rats by reducing tau phosphorylation, inflammatory cytokines, and neuronal apoptosis ^{78, 79}. Furthermore, cinnamon powder and sodium benzoate improved motor and cognitive function in transgenic mice with α-synucleinopathy, reduced α-synuclein accumulation, and upregulated neuroprotective proteins DJ-1 and Parkin ⁸⁰. C.cassia powder alleviated oxidative stress in the hippocampus of lupus-model mice by increasing p-NRF2/NRF2 and p-FOXO3/FOXO3 ratios ⁸¹.

Clinical Evidence: Despite numerous preclinical studies demonstrating the neuroprotective properties of cinnamon in animal models, studies involving human subjects are limited. Two recent studies have been reported.  In one of the studies, a 71-year-old female subject diagnosed with PD for more than 15 years, a combined therapy of cinnamon and honey demonstrated clinical improvement in the “on-time” administration along with oral pharmacological medicine ⁸². In another study ⁸³, 50 migraine patients who were given three daily 600 mg cinnamon capsules showed reduced inflammatory markers (NO, IL-6), fewer as well as less severe and shorter migraine attacks. These findings highlight cinnamon’s therapeutic potential in neurological disorders and inflammation-related conditions. However, specific, well-designed, randomized clinical trials are needed to validate these effects in larger populations.

Bioaccessability/ Bioavailability: Cinnamon is a potential natural pharmaceutical for the treatment of several health issues especially neurological disorders. However, the presence of blood brain barrier, the low bioavailability and fast systemic clearance of cinnamon biactives limit its in-vivo activities ⁸⁴. Several strategies are employed to enhance the bioavailability of cinnamon and its constituent compounds. Nano formulations and Encapsulation are reported to be the most effective ways in this direction.

Many encapsulation techniques, such as spray drying, coacervation, precipitation, freeze drying, ionic gelation, and ultrasonication, have been used recently to mitigate the limitations and improve the bioavailability of cinnamon bioactives ^{85, 86}. These methods are frequently used to distribute cinnamon bioactives, guaranteeing regulated release and improving functionality. Additionally, they enhance the solubility and stability of cinnamon's bioactive components even in harsh environmental conditions and protect them from degrading reactions.

Summary and Future Perspective: The cinnamon extracts, their bioactive compounds, and cinnamon oil exhibit significant neuroprotective effects and have been adequately demonstrated in various preclinical studies. Cinnamon alleviates neurodegeneration via different molecular mechanisms, involving antioxidant, anti-inflammatory, anti-amyloidogenic, regulation of apoptosis and autophagy-modulating properties Fig. 2 and 3.

Mechanistically, cinnamon bio-actives alleviate oxidative stress by enhancing the activity levels of antioxidant enzyme and mitigating ROS. They inhibit neuroinflammation by suppressing microglial activation and pro-inflammatory cytokines. Additionally, cinnamon bio-actives prevent tau aggregation and β-amyloid toxicity, which are crucial hallmarks of AD.

Moreover, cinnamaldehyde modulates autophagy via the mTORC1 pathway, facilitating protein clearance in neurodegenerative disorders. Several studies using Drosophila, C. elegans, and rodent models have also shown that cinnamon improves lifespan, cognitive function, and locomotor deficits in AD, PD, and rotenone-induced neurodegeneration.

FIG. 2: SCHEME DEPICTING THE DIFFERENT BIOACTIVE COMPONENTS OF CINNAMON AND THEIR PHARMACOLOGICAL PROPERTIES

FIG. 3: DIFFERENT MECHANISMS RESPONSIBLE FOR NEURO-MODULATORY POTENTIAL OF CINNAMON AND ITS BIO-ACTIVE COMPONENTS

CONCLUSION: While researchers have explored the multiple spectra of neuroprotective potential of cinnamon and its bioactives in the past decade in numerous preclinical models, only a few clinical studies have been attempted. Nevertheless, few preliminary trials have highlighted the potential cognitive benefits in mild cognitive impairment (MCI) and metabolic disorders linked to neurodegeneration. Further, clinical trials are necessary to establish cinnamon’s efficacy, optimal dosage, and safety following long-term intake in neurodegenerative diseases. Developing advanced drug delivery systems, such as nanoformulations and lipid-based carriers, can enhance their bioavailability and brain-targeting potential. In addition, exploring synergistic effects with existing neuroprotective agents may improve therapeutic outcomes. Investigating cinnamon’s role in the gut-brain axis and its influence on neuroinflammation could provide deeper insights. Further studies on its molecular mechanisms, including autophagy and mitochondrial function regulation, may help to establish cinnamon as a viable neuroprotective strategy.

ACKNOWLEDGEMENTS: Nil

CONFLICT OF INTEREST: The authors declare no conflict of interest.

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    Vismaya, Rajini PS and Muralidhara M: Neuroprotective potential of cinnamon: evidence from animal models, mechanistic insights, and therapeutic implications. Int J Pharm Sci & Res 2026; 17(2): 472-86. doi: 10.13040/IJPSR.0975-8232.17(2).472-86.

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