Anethum graveolens (dill) seeds are generally used as a spice, flavoring, and seasoning agent in food such as pickles, salads, etc. Dill essence is rich in flavonoids, a subclass of phytoestrogens that may be accountable for having positive effects on memory enhancement, increasing levels of acetylcholine (Mesripour et al. 2016), and displaying potent antioxidant activity [64]. The most abundant constituents of essential oils in seeds were found to be carvotanacetone (21.76  ±  1.62%), dill apiole (18.65  ±  1.89%), limonene (9.01  ±  1.11%), dill ether (9.13  ±  1.12%), 4-isopropyltoluene (8.24  ±  0.89%), and myrcene (7.44  ±  0.68%) [64].

The methanolic extract of A. graveolens seeds demonstrated moderate neuroprotective effects in PC12 cells treated with Aβ (25–35) aggregates with an ED50 value of 18.8 µg/mL [45]. The administration of A. graveolens ethanolic leaves extract significantly improved the learning and memory damage induced by scopolamine in Morris water maze and elevated plus maze experiments. A substantial decrease in AChE activity, increased activity of brain antioxidant enzymes such as superoxide dismutase, and decreased lipid peroxidation were also observed in the study. The most potent action was seen at a dose of 400 mg/Kg body weight [46].

The memory-enhancing activity of A. graveolens aqueous extract (100, 200, and 300 mg/Kg body weight) was also appraised by the conditioned avoidance response (CAR) technique in rats using Cook’s pole climbing apparatus [48]. Changes in cognition, retention, and recovery in rats were dose dependent. The extract also inhibited lipid peroxidation in both liver and brain tissues, suggesting the role of extract in reducing oxidative stress. In another study, the protective effect of A. graveolens aqueous extract was studied on hypercholesterolemia-induced cognitive deficits (HCDs) and oxidative stress in hippocampus tissues of rats [47,49]. HCD considerably augmented serum cholesterol levels, induced Aβ deposition, transformed morphology of hippocampus, and impaired memory function. However, the changes were reversed by administration of A. graveolens extract, which acted by increasing antioxidant levels in the brain, lowering serum cholesterol, retarding Aβ deposition, and normalizing hippocampal morphology.

PM52, a combined extract of Cissampelos pareira and A. graveolens, was evaluated against age-related cognitive impairment in a rat model. The data proposed that the cognitive-enhancing effect of PM52 might be due to suppression of AchE, resulting in increased levels of acetylcholine, a neurotransmitter that plays an important role in learning and memory and enriching neuron density in hippocampus by reducing the oxidative stress [50].

Hence, A. graveolens extracts and active constituents improved cognitive function in AD brain mainly by inhibiting AChE, improving oxidative stress conditions, and retarding amyloid β aggregation.

Carum carvi (caraway) is a biennial herb, the dried fruit of which is used as a spice due to its pleasing odor and sharp taste. The main components of essential oil are carvone (44.5–95.9%) and limonene (1.5–51.3%) and minor amounts of β-myrcene, trans-dihydrocarvone, trans-carveole (0–0.2%), α-pinene, sabinene, n-octanal, trans-β-ocimene, δ-terpinene, linalool, cis- and trans-limonene oxide, cis-dihydrocarvone, cis-carveol, perillaldehyde, trans-anethole, and trans-β-caryophyllene [65].

Microglia plays a dual role (neuroprotective or neurotoxic) in the progression of AD [66]. Microglia are regarded as initiators of neuroinflammation [67] and might play a role in the atypical networking in AD brain [68]. Various proinflammatory and neurotoxic substances, such as NO, iNOS, and COX-2, are produced by activated microglia. Therefore, reducing neuroinflammation by reducing microglia activation could be a promising therapeutic target in treatment of neuroinflammatory-mediated neurodegenerative diseases such as AD. It has already been reported that natural products with antineuroinflammatory activity are able to produce antiamyloid [69]. In an in vitro study, C. carvi aqueous extract was evaluated for its protective effects on LPS-activated neuroinflammation in BV-2 microglial cells. The extract inhibited LPS-induced phosphorylation/degradation of IκBα and translocation of NF-κB/p65 subunit in a concentration-dependent manner, which means the C. carvi extract plays an important role in regulating NF-κB signaling [51]. Carvone, the major component of C. carvi oil, is known to exhibit anti-inflammatory properties by inhibiting the synthesis of leukotrienes and prostaglandins [26]. Therefore, it is quite possible that carvone plays a role in modulation of the NF-κB pathway. Antioxidant, adaptogenic, and memory-enhancer activities of C. carvi aqueous extract were evaluated in rats using Cook’s pole climbing apparatus. The extract decreased lipid peroxidation in liver and brain homogenates [52]. Essential oil (EO) of C. carvi displayed strong in vitro anti-AChE activity (IC₅₀ = 0.82 ± 0.05 mg/mL) compared to the reference drug galantamine (IC₅₀ = 1.05 ± 0.05 mg/mL) [53]. Pharmacokinetics profiling of selected components of essential oils indicated their ability to penetrate the blood–brain barrier moderately (log BB values = 0.818–0.478). They also demonstrated high CaCO-2 permeability (log Papp values > 0.90 cm/s). All tested compounds were predicted neither substrates nor inhibitors of the human cytochrome P450 (CYP) isoforms. The boiled-egg graph (WLOGP vs. TPSA) prediction of GI absorption and BBB permeation, which helps in the calculation of polarity and lipophilicity, indicated that they possess a high probability of brain penetration [53].

Carvone, the main constituent of C. carvi, has been reported as an AChE inhibitor (IC₅₀ = 2.9 ± 0.12 mM) compared to the reference drug galantamine (IC₅₀ = 0.14 ± 0.005 mM) [27]. The inhibition is noncompetitive [70]. Additionally, docking studies revealed a putative H-bond interaction between the carvone and Tyr337 (2.92Å) of AChE, creating an anionic subsite. Other binding sites include Trp86, Tyr133, Tyr337, Phe338 (an anionic subsite), His447, Ser203 (an esteratic site), Gly121, Gly122 (oxyanion hole), Ile451, Gly448, Glu202, Gly120, and Ser125, all of which are most important portions of the AchE binding site [27]. In a recent study, (‒)-cis-carveol, a reduction product of carvone, improved Aβ_1-42-induced memory deficits in an animal model, examined by Y-maze and radial arm maze in vivo tests [71]. The biochemical analyses of the hippocampus homogenates showed a reduction in oxidative stress parameters caused by Aβ_1-42, suggesting the role of carveol in neuroprotection.

The second most important constituent in C. carvi is limonene, a monoterpene. Its protective role in spatial memory and anxiety has been established in a rat model exposed to immobilized stress [72]. Limonene also had a positive effect on scopolamine-induced amnesia, where it improved the modifications caused by scopolamine in a short-term memory test. It ameliorated the levels of oxidative stress markers (MDA, SOD, GSH) and inhibited AchE and BchE [20,37]. A study examined the effectiveness of limonene against Aβ_1-42-induced neurotoxicity in a Drosophila model of AD. The results showed that limonene suppressed the neuronal cell death induced by Aβ₄₂ and reduced oxidative stress, which prevented ERK phosphorylation [39]. In another study, the neuroprotective effect of limonene against neurotoxicity elicited by Aβ_1-42 in Hoechst 33,258 cell lines was observed. Limonene decreased ROS production and prevented the upregulation of Kv3.4 (voltage-gated potassium channel) activity at 10 µg/mL. This channel is overexpressed in AD and other neurodegenerative diseases [36]. Downregulation of Kv3.4 expression by limonene prevented cell death in primary cortical neurons, thus confirming its neuroprotective function in AD [38]. Moreover, limonene displayed a specific activity almost comparable to galantamine, the reference drug used against AchE.

Hence, maintaining the levels of antioxidant enzymes, inhibiting AchE, suppressing neuroinflammation and downregulating voltage-gated potassium channels are the main roles of C. carvi extract and active components in combating AD.

Coriandrum (coriander) is a feathery annual plant, used as both an herb and a spice. The main constituents of coriander oil are linalool (64.2−79.9%), γ-terpinene (5.8−13.6%), neryl acetate (2.3−8.4%), α-pinene (2.8−7.1%), and p-cymene (1.1−3.6%) [73]. In the Aβ_1-42 AD model, a test group of rats as made to inhale essential oil (1% and 3%) from C. sativum seed. Inhalation of essential oil considerably reduced levels of LDH and MDA, with an increase in glutathione peroxidase levels in the hippocampal region of rats. Additionally, there were fewer amyloid deposits in rats treated with EO. Specifically, linalool was found to be the active constituent in the EO; therefore, it can be speculated that linalool is responsible for cognitive-enhancing effects, along with antiapoptotic activities in Aβ_1-42-treated rats. The antioxidant defense, along with a decrease in lipid peroxidation, could be correlated with involvement of linalool in neuroprotection [40]. C. sativum seed extract is reported to be nontoxic in up to 3000 mg/kg body weight (BW) and, thus, can be considered safe for intake [74]. In a recent experiment, C. sativum seed extract (200 mg/Kg BW) improved memory impairment in senescence-accelerated mouse-prone 8 (SAMP8) mice. The mRNA levels of nNOS were higher in diseased the frontal lobe of diseased animals, which decreased significantly with the treatment of extract, suggesting that C. sativum can reduce the production of RNS and ROS and thus improve oxidative stress conditions. Moreover, the mRNA level of neurofilament light (NF-L), an important protein in memory retention and synaptic plasticity, was found lower in the frontal lobe and hippocampus of untreated mice, indicating neuronal damage. However, the mRNA levels NF-L were elevated after extract administration [54], indicating the role of C. sativum in neuroprotection. Previous studies have shown that α-pinene, γ-terpinene, and many monoterpenoids have anti-AchE activity [27,75,76]. As these phytocompounds are present in C. sativum, it is very much likely that its extract will also show anti-AchE activity.

Therefore, as described above, C. sativum extract and its bioactive compounds play an imperative role in neuroprotection by reducing ROS/RNS, elevating the level of an important protein involved in synaptic plasticity, and suppressing AchE activity.