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Salehi, A.; Ghanadian, M.; Zolfaghari, B.; Jassbi, A.R.; Fattahian, M.; Reisi, P.; Csupor, D.; Khan, I.A.; Ali, Z.; Ghanadian, M. Pharmacological Activities of Diterpenoid Alkaloids. Encyclopedia. Available online: https://encyclopedia.pub/entry/44554 (accessed on 16 August 2024).
Salehi A, Ghanadian M, Zolfaghari B, Jassbi AR, Fattahian M, Reisi P, et al. Pharmacological Activities of Diterpenoid Alkaloids. Encyclopedia. Available at: https://encyclopedia.pub/entry/44554. Accessed August 16, 2024.
Salehi, Arash, Mustafa Ghanadian, Behzad Zolfaghari, Amir Reza Jassbi, Maryam Fattahian, Parham Reisi, Dezső Csupor, Ikhlas A. Khan, Zulfiqar Ali, Mustafa Ghanadian. "Pharmacological Activities of Diterpenoid Alkaloids" Encyclopedia, https://encyclopedia.pub/entry/44554 (accessed August 16, 2024).
Salehi, A., Ghanadian, M., Zolfaghari, B., Jassbi, A.R., Fattahian, M., Reisi, P., Csupor, D., Khan, I.A., Ali, Z., & Ghanadian, M. (2023, May 19). Pharmacological Activities of Diterpenoid Alkaloids. In Encyclopedia. https://encyclopedia.pub/entry/44554
Salehi, Arash, et al. "Pharmacological Activities of Diterpenoid Alkaloids." Encyclopedia. Web. 19 May, 2023.
Pharmacological Activities of Diterpenoid Alkaloids
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This entry is adapted from the peer-reviewed paper 10.3390/ph16050747

Diterpenoid alkaloids (DAs) are characteristic components of some genera of the Ranunculaceae family, the occurrence of which is extraordinarily high in the genera Aconitum, Delphinium, and Consolida. To affect the central nervous system, primarily, the drug should pass the blood–brain barrier (BBB). Transmembrane diffusion is the most common route of drugs to pass the BBB and, in contrast to the transport system, shows a non-saturable kinetic. Physiochemical features of the drug mainly determine the amounts of this passage. Molecular weight (400–600 Da is optimum), lipid solubility, molecular charge, and tertiary structure are the most important factors necessary for transmembrane diffusion through BBB. The diterpenic backbone of DAs provides their suitable lipid solubility, but the presence of tertiary nitrogen makes them different from normal diterpenoids. The tertiary nitrogen with the highest proton affinity in the molecule (in water) rearranges the electronic structure of DA by its protonation. Moreover, computational modeling showed that the function of nitrogen besides ester sidechains causes DAs to interact with the active sites as well as their toxicity.

diterpene alkaloids Ranunculaceae neuropharmacology anticonvulsants

1. Anticonvulsant Effects

An abnormal and transient neuronal synchronization in the brain causes epilepsy. This phenomenon alters the correct pattern of neuronal connections and is characterized by the peaks and troughs of electric discharge in the electroencephalograph (EEG) and may lead to various mental and physical symptoms associated with the origin of the disruption [1]. Voltage-gated sodium channels (VGSCs) play an essential role in the generation and coordination of action potential in the central nervous system, which participates fundamentally in the pathophysiology of seizures; thus, these channels could be an important aim for pharmaco-therapy [2]. The Fuzi total alkaloids (Aconiti Lateralis Radix Praeparata), an essential medicine in traditional Chinese medicine, significantly prolong the seizure latency time and decrease the mortality in pentylenetetrazole-induced mice [3]. Additionally, anticonvulsant effects of several alkaloidal-rich fractions and also isolated DAs from Delphinium and Aconitum species have been investigated (Table 1; Figure 1). Ameri’s findings have greatly enhanced the knowledge of the anticonvulsant effects of DAs [4]. Five distinct toxin binding sites were explored on voltage-dependent Na+ channels. Aconitine (1), batrachotoxin, and veratridine are tightly bound to site 2 in the α subunit of Na+ channels which are localized in the transmembrane region [5][6][7]. The voltage-dependent Na+ channels are activated by 1, resulting in the depolarization of the presynaptic membrane [8]. Compound 1 activates Na+ channels at resting membrane potential permanently by blocking Na+ channel inactivation and causing hyperpolarization of threshold activation due to sustained Na+ influx; thereby, inexcitability occurs [4]. The structurally related 3-acetylaconitine (2) was shown to activate voltage-dependent Na+ channels by a similar mechanism of action [9]. In contrast to compounds 1 and 2, some other Aconitum DAs exist, revealing inhibitory effects on the Na+ channels; lappaconitine (3), N-desacetyllappaconitine (4), 6-benzoylheteratisine (5), and 1-benzoylnapelline (6) reduce the peak amplitude of the current and show an inhibitory effect on the Na+ channel [4]. While 3 could antagonize the suppressive effect of 1 on population spike in rat hippocampal slices which are attributed to their opposite mode of action; both 1 and 3 possess an anticonvulsant potential [5][10][11]. Compounds 1 and 2 indirectly suppressed the uptake of [3H] noradrenaline via increasing sodium concentration in synaptosomes, while 3 and 4 do not indicate such an impact on [3H] noradrenaline uptake [4][12]. Despite Ameri’s investigations, Voss et al. showed acute seizure-like activity induced by 1 [13]. Songorine (7) might antagonize the GABA receptor in the rat brain via a different site of action different from the GABA recognition site [14]. However, in an in vivo experiment, 7 acted as an agonist on D2 and GABA A receptors, which might be translated as a potential antiepileptic effect [15]. The involvement of α-adrenoceptors and modulation of GABA receptors were reported for the antiepileptic activity of mesaconitine (8) and Fuzi total alkaloid, respectively [3][16].
Figure 1. The chemical structures of the anticonvulsant diterpene alkaloids.
Table 1. Anticonvulsant effects of fractions/constituents from Aconitum and Delphinium species.
Plant Used Part/Constituents Biological Activity Affected In Vitro/In Vivo Model Ref.
Delphinium nordhagenii Acetone fraction Anticonvulsant activity Mice [17]
Aconitum violaceum Various fractions Anticonvulsant activity Mice [18]
Delphinium denudatum Aqueous fraction Antiepileptiform activity Cultured rat hippocampal pyramidal neurons [19]
Delphinium denudatum Aqueous fraction of roots Antiepileptiform activity Primary hippocampal neuronal cultures [20]
Delphinium denudatum Ethanolic extract and the aqueous fraction of roots Anticonvulsant activity Mice [21]
Aconitum carmichaeli Fuzi total alkaloids Increase the seizure latency and decrease the mortality Mice [3]
Aconitum sp. 6-Benzoyl deltamine (9) and eldeline (10) Antiepileptiform activity Rat hippocampal slices [22]
  1, 3, and ajacine (11) Antiepileptiform activity Rat hippocampal slices [10]
  5 Antiepileptiform activity Rat hippocampal slices [23]
  7 Increasing excitability Rat hippocampal slices [24]
  14-Benzoyl talatisamine (12) and talatisamine (13) Antiepileptiform activity Rat hippocampal slices [25]
  8 Antiepileptiform activity Rat hippocampal slices [16]
  8 10 nM evoked excitation
30–100 nM biphasic effect
above 100 nM suppressed the orthodromic population spike		 Rat hippocampal slices [26]
  1, 3, and 5 Antiepileptiform activity Rat hippocampal slices [27]
  3 and 4 Antiepileptiform activity Rat hippocampal slices [28]
  2 Antiepileptiform activity Rat hippocampal slices [9]
  1-Benzoyl napelline (14) Antiepileptiform activity Rat hippocampal slices [29]
  5 Antiepileptiform activity Rat hippocampal slices [30]
  5 and heteratisine (15) Antiepileptiform activity Rat hippocampal slices [31]
  1 Antiepileptiform activity Rat hippocampal slices [32]
  1 Prolonged seizure-like activity Neocortical slices from juvenile Sprague-Dawley rats [13]

2. Antagonizing α7 Nicotinic Acetylcholine Receptor

Nicotinic acetylcholine receptors (nAChRs) are cation-conducting ligand-gated receptors broadly expressed in the peripheral and central nervous systems and also in muscular cells. Seventeen nAChR subunits, comprising ten α, four β, γ, δ, and ε subunits have so far been identified in mammals where α7 homomeric nAChRs and heteromeric α4β2* nAChRs are predominant and expressed functionally in the brain. These receptors contribute to a range of neuronal functions from cognitive performance to neurotransmitter release (including glutamate, GABA, and dopamine) through altering intracellular Ca2+ concentration. It has been clarified that the pathogenesis of several neurological disorders containing Alzheimer’s disease, schizophrenia, Parkinson’s disease, and depression as well as nicotine addiction are related to α7 and α4β2* receptor functions. Although many efforts have been devoted to developing a (partial) agonist of α7 nAChR targeting neurologic and psychiatric conditions, none has already been approved as medicine due to their undesirable side effects [33][34][35]. Moreover, results from a meta-analysis indicated that curing the cognitive dysfunction in schizophrenia and Alzheimer’s disease with agonists of α7 nAChR cannot be considered a robust treatment [36]. In 1986, Jennings et al. found that the insecticidal effect of Delphinium plants is mainly due to the presence of methyllycaconitine (16) (Figure 2a), showing a high affinity to cholinergic receptors of insects [37]. Indeed, 16 is a potent and highly selective α7 nAChR antagonist which acts similarly to the α-bungarotoxin protein of snake venom (Figure 2b) [38]. Despite former research, sporadic studies have recently focused on the beneficial role which low doses of 16 play in neurologic disorders (Table 2); equivalent results were also reported for other nAChR antagonists, e.g., mecamylamine [39]. Several hypotheses have been proposed to explain their mechanism of action.
Figure 2. (a) Chemical structure of methyllycaconitine; (b) Homomeric α7 nicotinic acetylcholine receptor.
Table 2. Beneficial effects of low doses of methyllycaconitine (16) on neurologic functions.
Biological Activities Affected In Vitro/In Vivo Model Ref.
Picomolar concentration of 16 potentiated α7 nAChR activity/improved memory acquisition processes. Oocytes from mature Xenopus laevis females/rat [35]
Nanomolar concentrations of 16 acted as a co-agonist to potentiate TE-671 cell responses to acetylcholine, epibatidine, nicotine, and neostigmine. Rhabdomyosarcoma cell line TE-671 [40]
16 (0.4–1.3 mg/kg) improved response
accuracy at low doses.		 Rat model [41]
16 (1–4 mg/kg) significantly counteracted the learning impairment caused by dizocilpine. Rat model [42]
16 (1 mg/kg) significantly improved attentional function. Rat model [43]
Based on the allosteric theory of ion channel functioning, nAChRs might have three different conformational states, resting, active, and desensitized, having the capability of altering their conformational states through spontaneous transitions. Ligand affinity highly depends on conformational states. On the other hand, α7 nAChRs possess five binding sites for interacting with agonists, where binding to two of them is necessary for activating the receptor and opening the channel. Binding an antagonist, e.g., 16, to remaining binding sites may prevent or delay the desensitization of the receptor and affect the affinity of the receptor to other ligands. As a further explanation, the stoichiometry of the binding site with which the acetylcholine molecules (AChs) interact determines the degree of channel activation. The binding of two AChs to two consecutive binding sites leads to slow channel activation, while binding to two non-consecutive sites results in rapid activation and receptor desensitization. The binding of 16 impacts the binding pattern of ACh to sites. In case one, two, or three molecules of 16 connect to the binding sites, the probability of non-consecutive binding of ACh increases, whereas binding four and five molecules of 16 eliminates the possibility of simultaneous binding of two ACh molecules, which is essential for the activation of the receptor. The hypothesis explains the contradictory responses of α7 nAChR to lower and higher doses of 16 (Figure 3) [35].
Figure 3. Binding of methyllycaconitine could affect the binding pattern of ACh to binding sites and forms the three different conformational states. (a) The binding of two AChs to two consecutive binding sites leads to slow channel activation; (b) The binding of two AChs to two non-consecutive sites results in rapid activation and receptor desensitization; (c) Binding less than two AChs to binding sites causes a deactivation and the channel will be closed.

3. Analgesic Activity

Nociceptive pain develops in response to specific noxious stimulation of normal tissue in a normal somatosensory nervous system; in contrast, neuropathic pain comes from damage to the nerves or nervous system; there is also a third kind of pain called inflammatory pain, which may be described as increased sensitivity due to the inflammatory response associated with tissue damage [44]. Herbal preparations containing Aconitum have been widely used in traditional Chinese medicine to relieve rheumatoid arthritis [45]. The effectiveness of Aconitum-containing preparations for diabetic peripheral neuropathic pain was shown in a small clinical trial [46]. Pharmacological in vivo studies confirmed the antinociceptive activity of various DAs and extracts from Aconitum species (Table 3; Figure 4). Bulleyaconitine A (17), a diterpenoid alkaloid isolated from the rhizomes of A. bulleyanum, is structurally related to 1 and was approved in 1985 in China for the alleviation of chronic pain and is available as tablets, intramuscular injections, and soft gel capsules [47]. Compound 17 showed more significant analgesic potency than morphine. The clinical utility of 17 in the three past decades in China has demonstrated the advantages of its application for relieving chronic pain without any serious side effects, contrary to what is observed in the case of the application of morphine or non-steroidal analgesics [48]. Several studies have emphasized the positive central effect of 17 in the treatment of nociceptive pains [34]. The analgesic effect of 17 could be antagonized by reserpine but not naloxone, which suggests an involvement of catecholamine in the 17 mechanisms of action [49]. Compound 7 revealed a visceral antinociceptive effect by stimulating the release of dynorphin A, leading to the activation of presynaptic κ-opioid receptors in afferent neurons [37]. Consistently, it was indicated that 17 can directly stimulate the dynorphin A expression in spinal microglia [50]. On the other hand, Xie et al. suggested a preferable blocking effect on tetrodotoxin-sensitive Nav1.7 and Nav1.3 in dorsal root ganglion neurons as the mode of action of 17 [51]. Compound 17 could also inhibit Nav1.7 and Nav1.8 Na+ currents in a use-dependent manner [52]. Depressing of long-term potentiation at C-fiber synapses in the spinal dorsal horn and inhibition of transmitter release in paclitaxel-induced neuropathic pain were accounted for as well [53].
Figure 4. Chemical structures of the analgesic DAs.
Another diterpenoid alkaloid, lappaconitine (3) from Aconitum species revealed antinociceptive effects in nociceptive test models. Compound 3 has been used for its analgesic properties in both traditional Chinese and Kampo medicine [54]. Its analgesic potency is comparable to that of tramadol and morphine [55][56]. Pretreatment with antagonists of adrenergic and serotoninergic systems could decrease the antinociceptive effects of 3, which might be mediated by β-adrenoceptors and 5-HT2 receptors in the brain and α-adrenoceptors and 5-HT receptors in the spinal cord [57]. Moreover, when 3 was administered via subcutaneous or intracerebroventricular routes, it could inhibit behavioral response induced by substance P or somatostatin, while the intrathecal injection showed no effect. These observations provide some evidence to support the supra-spinal descending mechanism of action of 3 and suppressing the transmission of the nociceptive neuronal message [58]. Inhibition of P2X(4) expression in microglia in the dorsal horn and P2X3 receptors in dorsal root ganglia neurons in the spinal cord were demonstrated as further plausible mechanisms of action [59][60][61]. Li et al. indicated that inhibition of the Nav1.7 channel is involved as well [62]. Similar to 17 stimulation of the expression of spinal microglial dynorphin A was suggested [63]. Ono et al. indicated that the antinociceptive effect of 3 was not antagonized by naloxone in the hot plate and acetic acid-induced writing tests, contrary to what was observed in the tail pinch test. It was suggested that the action of 3 was only partially antagonized by naloxone, which explains the naloxone-resistant antinociceptive activity for 3 at the spinal sites [64].
Mesaconitine (8), one of the most important ingredients of Aconitum species, also exhibits antinociceptive activity in animal models. Subcutaneous administration of 8 has shown much greater analgesic activity compared to that of morphine in animal models [65]. Friese et al. categorized Aconitum alkaloids into two groups based on their binding affinity to Na+ channel epitope site 2. Alkaloids of the high-affinity group (1 and 8) are supposed to act as Na+ activators due to their increasing synaptosomal [Na+]i and [Ca2+]i effect. A higher antinociceptive action was shown in the case of the high-affinity group than the other, indicating the importance of Na+ channels in the activity of 8 [66]. The analgesic action of 8 was not inhibited by levallorphan (an opiate antagonist) in an animal model. On the other hand, 8 could increase the release of endogenous norepinephrine from sympathetic nerve fibers [65]. Application cyclic AMP and isoproterenol (a β receptor agonist) in combination with 8 enhanced its analgesic activity, while propranolol (a β receptor antagonist) suppressed it, which magnifies the role of the adrenergic system in the mode of action [67]. Involvement of the nucleus reticularis gigantocellularis (NRGC), the nucleus reticularis paragigantocellularis (NRPG), the periaqueductal gray (PAG), and the lumbar enlargement in the antinociceptive action of 8 was shown in a rat model. Indeed, 8 might activate the inhibitory noradrenergic system in descending neurons from the NRPG, especially through β-receptor-mediated effects of noradrenaline [57][58]. Moreover, it was also revealed that the nucleus raphe magnus (NRM) has a key role via the serotoninergic system in the mechanism of action [68].
Isotalatizidine (18) attenuates allodynia in neuropathic pain in a mice model. An increase in the expression of dynorphin A was shown, and its release from microglia was observed, which might be triggered by the activation of the ERK1/2 pathway and phosphorylation of CREB (cAMP response element-binding) [69].
Bullatine A (19) was shown to have a synergistic effect with morphine as it increases morphine analgesic action while counteracting morphine tolerance. Stimulation of spinal microglia and subsequent enhancing of the expression of dynorphin A were thought to have a role [70][71].
Table 3. Antinociceptive effects of fractions/constituents from Aconitum and Delphinium species.
Plant Used Part/Constituents Biological Activity Ref.
Aconitum episcopale Episcopaline B (20) Antinociceptive effect 2-fold lower than aspirin and
acetaminophen		 [72]
Aconitum pseudostapfianum Pseudostapine C (21) 2-fold more potent antinociceptive effect than
aspirin and acetaminophen		 [73]
Aconitum episcopale Episcopine A (22) 2-fold more potent antinociceptive effect than aspirin and acetaminophen [74]
Aconitum
carmichaelii		 18 Antinociceptive effect [69]
Aconitum carmichaeli Plant extract and neoline (23) Attenuated the mechanical hyperalgesia [75]
Aconitum carmichaeli Plant extract and 23 Attenuated cold and mechanical hyperalgesia [76]
Aconitum carmichaeli Aqueous extracts Antinociceptive activity [77]
Aconitum carmichaeli Processed aconitum tuber High doses of processed Aconiti tuber inhibit the acute but potentiate the chronic antinociception of morphine [78]
Delphinium denudatum Aqueous root extract Antinociceptive activity [79]
Aconitum carmichaeli Processed aconitum tuber and 8 Antinociceptive activity of 8 was more potent than morphine [80]
Aconitum sp. 1 Significant analgesic effects [81]
Aconitum carmichaelii Aconicatisulfonines A (24) and B (25) Analgesic activities [82]
Delphinium denudatum Ethanolic extract and methanol fraction Analgesic activity [83]
Aconitum kusnezoffii 23 Analgesic activity [84]
Aconitum carmichaelii Aconicarmichosides E (26), F (27), H (28), I (29), and J (30) Analgesic activity [85]
Aconitum sp. 3 Relieves the pain [53]
Aconitum baikalensis Napelline (31), hypaconitine (32), 7, 8, 12-epinapelline N-oxide (33). Analgesic activity comparable to that of sodium metamizole [86]
Aconitum
weixiense		 Weisaconitines D (34) Analgesic activity [87]
Aconitum
carmichaeli		 Guiwuline (35) Potential analgesic activity [88]
Aconitum
carmichaeli		 8-O-cinnamoylneoline (36) Analgesic activity [89]

4. Antidementia Effect

A decrease in acetylcholine (ACh) in the central nervous system is associated with dementia. Several DAs possess an acetylcholinesterase (AChE) inhibitory effect (Table 4; Figure 5), and therefore, these compounds may theoretically act as antidementia agents. Some evidence has emphasized the role of K+ channel blockers as drug candidates for the treatment of neurodegenerative disorders [90]. Virtual screening from the Chinese natural product database resulted in the identification of four Aconitum alkaloids, namely, songorine (7), pyrochasmaconitine (37), 14-benzoyl talatisamine (12), and talatisamine (13), as candidates for this effect; an electrophysiological assay of rat dissociated hippocampal neurons verified this assumption [91]. All of the four alkaloids potently inhibited the delayed rectifier K+ current, while 13 was slightly effective on Na+ and Ca2+ channels in rat hippocampal neurons [90].
Figure 5. Chemical structures of diterpene alkaloids with antidementia activity.
Macroautophagy was previously considered one of the plausible mechanisms of the pathogenesis of Alzheimer’s disease (AD). Compound 16 protects the human neuroblastoma SH-SY5Y cell line against amyloid-β peptide-induced cytotoxicity. Compound 16 might prevent autophagy induced by amyloid-β through the mammalian target of the rapamycin (m-tor) pathway [92]. Apetalrine B (38), the semisynthetic DAs from its parent compound, aconorine (A. apetalum), exhibits a neuroprotective effect in H2O2-treated SH-SY5Y cells by inhibiting cell apoptosis [93]. Firstly, 7 was superior to piracetam (a nootropic agent) in the correction of the cholinergic abnormalities induced by scopolamine, which indicates its antiamnestic activity. Secondly, 7 might act as a cholinomimetic, antihypoxic, and cerebro-protective agent [94][95]. Among the DAs from A. anthoroideum, rotundifosine F (39) possesses AChE inhibitory activity. Moreover, nominine (40) represented a neuroprotective effect due to its protection against 1-methyl-4-phenylpyridinium (MPP+)-induced apoptosis in SH-SY5Y cells [96]. Fuzi considerably induced growth of cell projection and cell proliferation in 0.4–0.8 mg/mL and 1.6–100 mg/mL, respectively, in the AD cell model. In addition, the involvement of GRIN1 and MAPK1 genes contributed to the antiAD mechanism of action [97].
Table 4. Antidementia effect of fractions/constituents from Aconitum and Delphinium species.
Plant Used Part/Constituents Biological Activity Ref.
Aconitum hemsleyanum Hemsleyaline (41) Mild AChE inhibitory effect [98]
Aconitum kirinense Diterpenoid alkaloids Moderate AChE inhibitory effect [99]
Aconitum laeve Diterpenoid alkaloids Swatinine-C (42) and hohenackerine (43)
competitively inhibited AChE and BChE
Aconorine (44) and 3 noncompetitively inhibited AChE		 [100]
Delphinium denudatum Diterpenoid alkaloids Jadwarine-A (45), 18, and dihydropentagynine (46) competitively inhibited AChE and BChE, while 1β-hydroxy,14β-acetyl condelphine (47) and jadwarine-B (48) showed non-competitive inhibition [101]
Aconitum heterophyllum Diterpenoid alkaloids Compounds 6b-methoxy, 9b-dihydroxylheteratisine (49), 6,15b-dihydroxylhetisine (50), iso-atisine (51), heteratisine, 19-epi-isoatisine (52), and atidine (53) non-competitively inhibited AChE and BChE, while compounds 1a,11,13b-trihydroxylhetisine (54) and hetisinone (55) were determined as competitive inhibitors [102]
Delphinium denudatum Isotalatizidine (18) hydrate Potent dual cholinesterase inhibitor [103]
Aconitum heterophyllum Heterophyllinine A(56) and B (57) 56 and 57 inhibited AChE and BChE enzymes [104]
Aconitum falconeri Faleoconitine (58)
and Pseudaconitine (59)		 Moderate inhibitory activity on AChE [105]

5. Antidepressant Effects

Two antagonists of nicotinic acetylcholine receptor (nAChR) were demonstrated to induce antidepressant effects in the forced swim and tail suspension tests in mice, while agonists of nAChR did exhibit no similar activity. The observed effect was more potent in the case of the non-selective nAChR antagonist mecamylamine compared to that of 16 (an α7 nAChR selective antagonist) [106]. Modulating serotonin sensitivity is considered a promising mechanism of action of DAs’ antidepressant activity in Aconitum baicalense. Besides their positive results in the tail suspension test, these compounds showed an antiexudative effect in edema induced by serotonin in mice. These alkaloids were 7, 8, 32, and 31 in order from most to least potent [107]. Antidepressant actions were also reported for chronic administration of Fuzi total alkaloids in normal and ovariectomized mice. An study designed to elucidate the mode of action discovered the potential roles of cAMP response element-binding (CREB) and brain-derived neurotrophic factor (BDNF) protein pathways [108]. Moreover, the sex-dependent antidepressant effect of 16 was consistently reported in male mice, while female mice did not exhibit the same. Local administration of 16 in male mice hippocampus could reverse the depression-like effect which was induced by physostigmine [109].

6. Miscellaneous Effects

Compound 7 has exhibited a more potent anxiolytic activity compared to phenazepam applying the Vogel conflict test in mice without a sedative effect. Anxiolytic activity of 7 was noted in a dose of 0.25 mg/kg, while a 10 times higher dose (2.5 mg/kg) showed an inferior activity [110].
An ethanolic extract of Delphinium denudatum has protected the brain against injury in a rat model of Parkinson’s disease. The expression of ipsilateral tyrosine hydroxylase was increased. The extract also prevented lipid peroxidation, depleted reduced glutathione in the substantia nigra, and attenuated the activity of superoxide dismutase and catalase in the striatum. Reduction in dopamine concentration was also reported in the striatum after the injection of 6-hydroxydopamine [111].

References

  1. Moshé, S.L.; Perucca, E.; Ryvlin, P.; Tomson, T. Epilepsy: New advances. Lancet 2015, 385, 884–898.
  2. Kaplan, D.I.; Isom, L.L.; Petrou, S. Role of Sodium Channels in Epilepsy. Cold Spring Harb. Perspect. Med. 2016, 6, a022814.
  3. Li, B.; Tang, F.; Wang, L.; Liu, L.; Zhao, J.; Zhou, Y.; Wang, Y.; Song, Y.; Li, Y.; Cui, R. Anticonvulsant Effects of Fuzi Total Alkaloid on Pentylenetetrazole-Induced Seizure in Mice. J. Pharmacol. Sci. 2013, 123, 195–198.
  4. Ameri, A. The effects of Aconitum alkaloids on the central nervous system. Prog. Neurobiol. 1998, 56, 211–235.
  5. Catterall, W.A. Structure and Function of Voltage-Sensitive Ion Channels. Science 1988, 242, 50–61.
  6. Catterall, W.A. Cellular and molecular biology of voltage-gated sodium channels. Physiol. Rev. 1992, 72, S15–S48.
  7. Adams, M.E.; Olivera, B.M. Neurotoxins: Overview of an emerging research technology. Trends Neurosci. 1994, 17, 151–155.
  8. Yamanaka, H.; Doi, A.; Ishibashi, H.; Akaike, N. Aconitine facilitates spontaneous transmitter release at rat ventromedial hypothalamic neurons. Br. J. Pharmacol. 2002, 135, 816–822.
  9. Ameri, A. Inhibition of rat hippocampal excitability by the plant alkaloid 3-acetylaconitine mediated by interaction with voltage-dependent sodium channels. Naunyn-Schmiedeberg’s Arch. Pharmacol. 1997, 355, 273–280.
  10. Ameri, A.; Simmet, T. Antagonism of the aconitine-induced inexcitability by the structurally related Aconitum alkaloids, lappaconitine and ajacine. Brain Res. 1999, 842, 332–341.
  11. Ameri, A.; Shi, Q.; Aschoff, J.; Peters, T. Electrophysiological effects of aconitine in rat hippocampal slices. Neuropharmacology 1996, 35, 13–22.
  12. Seitz, U.; Ameri, A. Different Effects on Noradrenaline Uptake of the Aconitum Alkaloids Aconitine, 3-Acetylaconitine, Lappaconitine, and N-Desacetyllappaconitine in Rat Hippocampus. Biochem. Pharmacol. 1998, 55, 883–888.
  13. Voss, L.J.; Voss, J.M.; McLeay, L.; Sleigh, J.W. Aconitine induces prolonged seizure-like events in rat neocortical brain slices. Eur. J. Pharmacol. 2008, 584, 291–296.
  14. Zhao, X.-Y.; Wang, Y.; Li, Y.; Chen, X.-Q.; Yang, H.-H.; Yue, J.-M.; Hu, G.-Y. Songorine, a diterpenoid alkaloid of the genus Aconitum, is a novel GABAA receptor antagonist in rat brain. Neurosci. Lett. 2003, 337, 33–36.
  15. Koszegi, Z.; Atlasz, T.; Csupor, D.; Hohmann, J.; Hernadi, I. Aconitum alkaloid songorine acts as a potent GABAA receptor agonist in the rat brain in vivo. Acta Neurobiol. Exp. Wars. 2007, 94, 367–368.
  16. Ameri, A. Effects of the Aconitum alkaloid mesaconitine in rat hippocampal slices and the involvement of α-and β-adrenoceptors. Br. J. Pharmacol. 1998, 123, 243–250.
  17. Raza, M.L.; Zeeshan, M.; Ahmad, M.; Shaheen, F.; Simjee, S.U. Anticonvulsant activity of DNS II fraction in the acute seizure models. J. Ethnopharmacol. 2010, 128, 600–605.
  18. Raza, M.; Zeeshan, M.; Ahmad, M.; Shaheen, F.; Simjee, S. Anticonvulsant activity of Aconitum violaceum against maximal electroshock induced seizure model. Behv Pharm. 2008, 19, 658–659.
  19. Raza, M.; Shaheen, F.; Choudhary, M.I.; Sombati, S.; Rahman, A.-U.; DeLorenzo, R.J. Inhibition of sustained repetitive firing in cultured hippocampal neurons by an aqueous fraction isolated from Delphinium denudatum. J. Ethnopharmacol. 2004, 90, 367–374.
  20. Raza, M.; Shaheen, F.; Choudhary, M.I.; Rahman, A.-U.; Sombati, S.; DeLorenzo, R.J. In vitro inhibition of pentylenetetrazole and bicuculline-induced epileptiform activity in rat hippocampal pyramidal neurons by aqueous fraction isolated from Delphinium denudatum. Neurosci. Lett. 2002, 333, 103–106.
  21. Raza, M.; Shaheen, F.; Choudhary, M.I.; Sombati, S.; Rafiq, A.; Suria, A.; Rahman, A.-U.; DeLorenzo, R.J. Anticonvulsant activities of ethanolic extract and aqueous fraction isolated from Delphinium denudatum. J. Ethnopharmacol. 2001, 78, 73–78.
  22. Ameri, A.; Zimmermann, T.; Simmet, T. Frequency- and structure-dependent inhibition of normal and epileptiform activity by 6-benzoyldeltamine in rat hippocampal slices. Eur. J. Pharmacol. 1999, 369, 279–288.
  23. Ameri, A.; Simmet, T. Interaction of the structurally related Aconitum alkaloids, aconitine and 6-benzyolheteratisine, in the rat hippocampus. Eur. J. Pharmacol. 1999, 386, 187–194.
  24. Ameri, A. Effects of the Aconitum alkaloid songorine on synaptic transmission and paired-pulse facilitation of CA1 pyramidal cells in rat hippocampal slices. Br. J. Pharmacol. 1998, 125, 461–468.
  25. Ameri, A. Structure-dependent inhibitory action of the Aconitum alkaloids 14-benzoyltalitasamine and talitasamine in rat hippocampal slices. Naunyn-Schmiedeberg’s Arch. Pharmacol. 1998, 357, 585–592.
  26. Ameri, A. Inhibition of stimulus-triggered and spontaneous epileptiform activity in rat hippocampal slices by the Aconitum alkaloid mesaconitine. Eur. J. Pharmacol. 1998, 342, 183–191.
  27. Ameri, A.; Gleitz, J.; Peters, T. Inhibition of neuronal activity in rat hippocampal slices by Aconitum alkaloids. Brain Res. 1996, 738, 154–157.
  28. Ameri, A. Structure-dependent differences in the effects of the Aconitum alkaloids lappaconitine, N-desacetyllappaconitine and lappaconidine in rat hippocampal slices. Brain Res. 1997, 769, 36–43.
  29. Ameri, A. Inhibition of rat hippocampal excitability by the Aconitum alkaloid, 1-benzoylnapelline, but not by napelline. Eur. J. Pharmacol. 1997, 335, 145–152.
  30. Ameri, A. Electrophysiological actions of the plant alkaloid 6-benzoylheteratisine in rat hippocampal slices. Naunyn-Schmiedeberg’s Arch. Pharmacol. 1997, 355, 538–544.
  31. Ameri, A. Effects of the alkaloids 6-benzoylheteratisine and heteratisine on neuronal activity in rat hippocampal slices. Neuropharmacology 1997, 36, 1039–1046.
  32. Ameri, A.; Gleitz, J.; Peters, T. Aconitine inhibits epileptiform activity in rat hippocampal slices. Naunyn-Schmiedeberg’s Arch. Pharmacol. 1996, 354, 80–85.
  33. Ho, T.N.T.; Abraham, N.; Lewis, R.J. Structure-Function of Neuronal Nicotinic Acetylcholine Receptor Inhibitors Derived from Natural Toxins. Front. Neurosci. 2020, 14, 609005.
  34. Dineley, K.T.; Pandya, A.A.; Yakel, J.L. Nicotinic ACh receptors as therapeutic targets in CNS disorders. Trends Pharmacol. Sci. 2015, 36, 96–108.
  35. Van Goethem, N.P.; Paes, D.; Puzzo, D.; Fedele, E.; Rebosio, C.; Gulisano, W.; Palmeri, A.; Wennogle, L.P.; Peng, Y.; Bertrand, D.; et al. Antagonizing α7 nicotinic receptors with methyllycaconitine (MLA) potentiates receptor activity and memory acquisition. Cell. Signal. 2019, 62, 109338.
  36. Lewis, A.S.; van Schalkwyk, G.I.; Bloch, M.H. Alpha-7 nicotinic agonists for cognitive deficits in neuropsychiatric disorders: A translational meta-analysis of rodent and human studies. Prog. Neuro Psychopharmacol. Biol. Psychiatry 2017, 75, 45–53.
  37. Jennings, K.R.; Brown, D.G.; Wright, D.P. Methyllycaconitine, a naturally occurring insecticide with a high affinity for the insect cholinergic receptor. Experientia 1986, 42, 611–613.
  38. Daly, J.W. Nicotinic Agonists, Antagonists, and Modulators from Natural Sources. Cell. Mol. Neurobiol. 2005, 25, 513–552.
  39. Levin, E.D.; Caldwell, D.P. Low-dose mecamylamine improves learning of rats in the radial-arm maze repeated acquisition procedure. Neurobiol. Learn. Mem. 2006, 86, 117–122.
  40. Green, B.T.; Welch, K.D.; Cook, D.; Gardner, D.R. Potentiation of the actions of acetylcholine, epibatidine, and nicotine by methyllycaconitine at fetal muscle-type nicotinic acetylcholine receptors. Eur. J. Pharmacol. 2011, 662, 15–21.
  41. Hahn, B.; Shoaib, M.; Stolerman, I.P. Selective nicotinic receptor antagonists: Effects on attention and nicotine-induced attentional enhancement. Psychopharmacology 2011, 217, 75–82.
  42. Burke, D.A.; Heshmati, P.; Kholdebarin, E.; Levin, E.D. Decreasing nicotinic receptor activity and the spatial learning impairment caused by the NMDA glutamate antagonist dizocilpine in rats. Eur. J. Pharmacol. 2014, 741, 132–139.
  43. Levin, E.D.; Cauley, M.; Rezvani, A.H. Improvement of attentional function with antagonism of nicotinic receptors in female rats. Eur. J. Pharmacol. 2013, 702, 269–274.
  44. Xie, M.-X.; Zhu, H.-Q.; Pang, R.-P.; Wen, B.-T.; Liu, X.-G. Mechanisms for therapeutic effect of bulleyaconitine A on chronic pain. Mol. Pain 2018, 14, 1744806918797243.
  45. Singhuber, J.; Zhu, M.; Prinz, S.; Kopp, B. Aconitum in Traditional Chinese Medicine-A valuable drug or an unpredictable risk? J. Ethnopharmacol. 2009, 126, 18–30.
  46. Feng, L.; Liu, W.-K.; Deng, L.; Tian, J.-X.; Tong, X.-L. Clinical Efficacy of Aconitum-Containing Traditional Chinese Medicine for Diabetic Peripheral Neuropathic Pain. Am. J. Chin. Med. 2014, 42, 109–117.
  47. Huang, S.-N.; Wei, J.; Huang, L.-T.; Ju, P.-J.; Chen, J.; Wang, Y.-X. Bulleyaconitine A Inhibits Visceral Nociception and Spinal Synaptic Plasticity through Stimulation of Microglial Release of Dynorphin A. Neural Plast. 2020, 2020, 1484087.
  48. Liu, Y.Q.; Ding, X.N.; Wang, Y.D. The clinical studies of BLA tablets to treat common chronic pain. Chin. J. Pain. Med. 2011, 17, 314–315.
  49. Tang, X.C.; Liu, X.J.; Lu, W.H.; Wang, M.D.; Li, A.L. Studies on the analgesic action and physical dependence of bulleyaconitine A. Yao Xue Xue Bao Acta Pharm. Sin. 1986, 21, 886–891.
  50. Li, T.-F.; Fan, H.; Wang, Y.-X. Aconitum-Derived Bulleyaconitine A Exhibits Antihypersensitivity through Direct Stimulating Dynorphin A Expression in Spinal Microglia. J. Pain 2016, 17, 530–548.
  51. Xie, M.-X.; Yang, J.; Pang, R.-P.; Zeng, W.-A.; Ouyang, H.-D.; Liu, Y.Q.; Liu, X.-G. Bulleyaconitine A attenuates hyperexcitability of dorsal root ganglion neurons induced by spared nerve injury: The role of preferably blocking Nav1.7 and Nav1.3 channels. Mol. Pain 2018, 14, 1744806918778491.
  52. Wang, C.-F.; Gerner, P.; Schmidt, B.; Xu, Z.Z.; Nau, C.; Wang, S.-Y.; Ji, R.-R.; Wang, G.K. Use of Bulleyaconitine A as an Adjuvant for Prolonged Cutaneous Analgesia in the Rat. Anesth. Analg. 2008, 107, 1397–1405.
  53. Zhu, H.-Q.; Xu, J.; Shen, K.-F.; Pang, R.-P.; Wei, X.-H.; Liu, X.-G. Bulleyaconitine A depresses neuropathic pain and potentiation at C-fiber synapses in spinal dorsal horn induced by paclitaxel in rats. Exp. Neurol. 2015, 273, 263–272.
  54. Nyirimigabo, E.; Xu, Y.; Li, Y.; Wang, Y.; Agyemang, K.; Zhang, Y. A review on phytochemistry, pharmacology and toxicology studies of Aconitum. J. Pharm. Pharmacol. 2015, 67, 1–19.
  55. Ono, M.; Satoh, T. Pharmacological studies of lappaconitine. Analgesic activities. Arzneimittelforschung 1988, 38, 892–895.
  56. Gong, Q.-A.; Li, M. Effect of Lappaconitine on Postoperative Pain and Serum Complement 3 and 4 Levels of Cancer Patients Undergoing Rectum Surgery. Zhongguo Zhong Xi Yi Jie He Za Zhi Zhongguo Zhongxiyi Jiehe Zazhi Chin. J. Integr. Tradit. West. Med. 2015, 35, 668–672.
  57. Ono, M.; Satoh, T. Pharmacological Studies on Lappaconitine: Possible Interaction with Endogenous Noradrenergic and Serotonergic Pathways to Induce Antinociception. Jpn. J. Pharmacol. 1992, 58, 251–257.
  58. Ono, M.; Satoh, T. Pharmacological studies on lappaconitine: Antinociception and Inhibition of the Spinal Action of Substance P and Somatostatin. Jpn. J. Pharmacol. 1991, 55, 523–530.
  59. Zhao, D.-K.; Shi, X.-Q.; Zhang, L.-M.; Yang, D.-Q.; Guo, H.-C.; Chen, Y.-P.; Shen, Y. Four new diterpenoid alkaloids with antitumor effect from Aconitum nagarum var. heterotrichum. Chin. Chem. Lett. 2017, 28, 358–361.
  60. Yang, C.L.; Wei, Z.R.; Zhang, T.H.; Zeng, X.Q.; Wu, B.H. Effects of lappaconitine on pain and inflammatory response of severely burned rats and the mechanism. Zhonghua Shao Shang Za Zhi Zhonghua Shaoshang Zazhi Chin. J. Burn. 2017, 33, 374–380.
  61. Ou, S.; Zhao, Y.-D.; Xiao, Z.; Wen, H.-Z.; Cui, J.; Ruan, H.-Z. Effect of lappaconitine on neuropathic pain mediated by P2X3 receptor in rat dorsal root ganglion. Neurochem. Int. 2011, 58, 564–573.
  62. Li, Y.F.; Zheng, Y.M.; Yu, Y.; Gan, Y.; Gao, Z.B. Inhibitory effects of lappaconitine on the neuronal isoforms of voltage-gated sodium channels. Acta Pharmacol. Sin. 2019, 40, 451–459.
  63. Sun, M.-L.; Ao, J.-P.; Wang, Y.-R.; Huang, Q.; Li, T.-F.; Li, X.-Y.; Wang, Y.-X. Lappaconitine, a C18-diterpenoid alkaloid, exhibits antihypersensitivity in chronic pain through stimulation of spinal dynorphin A expression. Psychopharmacology 2018, 235, 2559–2571.
  64. Ono, M.; Satoh, T. Pharmacological studies of lappaconitine. Analgesia produced by intracerebroventricular, intracisternal and intrathecal injections. J. Pharm. Dyn. 1990, 13, 374–377.
  65. Murayama, M.; Ito, T.; Konno, C.; Hikino, H. Mechanism of analgesic action of mesaconitine. I. Relationship between analgesic effect and central monoamines or opiate receptors. Eur. J. Pharmacol. 1984, 101, 29–36.
  66. Friese, J.; Gleitz, J.; Gutser, U.T.; Heubach, J.F.; Matthiesen, T.; Wilffert, B.; Selve, N. Aconitum sp. alkaloids: The modulation of voltage-dependent Na+ channels, toxicity and antinociceptive properties. Eur. J. Pharmacol. 1997, 337, 165–174.
  67. Hikino, H.; Murayama, M. Mechanism of the antinociceptive action of mesaconitine: Participation of brain stem and lumbar enlargement. Br. J. Pharmacol. 1985, 85, 575–580.
  68. Suzuki, Y.; Oyama, T.; Ishige, A.; Isono, T.; Asami, A.; Ikeda, Y.; Noguchi, M.; Omiya, Y. Antinociceptive Mechanism of the Actonitine Alkaloids Mesaconitine and Benzoylmesaconine. Planta Med. 1994, 60, 391–394.
  69. Shao, S.; Xia, H.; Hu, M.; Chen, C.; Fu, J.; Shi, G.; Guo, Q.; Zhou, Y.; Wang, W.; Shi, J.; et al. Isotalatizidine, a C19-diterpenoid alkaloid, attenuates chronic neuropathic pain through stimulating ERK/CREB signaling pathway-mediated microglial dynorphin A expression. J. Neuroinflammation 2020, 17, 13.
  70. Huang, Q.; Mao, X.-F.; Wu, H.-Y.; Li, T.-F.; Sun, M.-L.; Liu, H.; Wang, Y.-X. Bullatine A stimulates spinal microglial dynorphin A expression to produce anti-hypersensitivity in a variety of rat pain models. J. Neuroinflammation 2016, 13, 214.
  71. Huang, Q.; Sun, M.-L.; Chen, Y.; Li, X.-Y.; Wang, Y.-X. Concurrent bullatine A enhances morphine antinociception and inhibits morphine antinociceptive tolerance by indirect activation of spinal κ-opioid receptors. J. Ethnopharmacol. 2017, 196, 151–159.
  72. Hu, J.; Li, J.X.; Li, Q.; Mao, X.; Peng, T.F.; Liu, H.Q.; Yin, S.; Yuan, H.J. Antinociceptive C19–diterpenoid alkaloids from the root of Aconitum episcopale. J. Asian Nat. Prod. Res. 2022, 24, 617–623.
  73. Hu, J.; Li, J.X.; Li, Q.; Mao, X.; Peng, T.F.; Jin, N.H.; Yin, S.; Tang, Y. Antinociceptive C19–diterpenoid alkaloids isolated from Aconitum pseudostapfianum. J. Asian Nat. Prod. Res. 2021, 23, 637–643.
  74. Hu, J.; Li, J.; Li, Q.; Mao, X.; Peng, T.; Jin, N.; Yin, S.; Shi, X.; Li, Y. Antinociceptive C19-Diterpenoid Alkaloids from Aconitum episcopale. Chem. Nat. Compd. 2021, 57, 503–506.
  75. Tanimura, Y.; Yoshida, M.; Ishiuchi, K.; Ohsawa, M.; Makino, T. Neoline is the active ingredient of processed aconite root against murine peripheral neuropathic pain model, and its pharmacokinetics in rats. J. Ethnopharmacol. 2019, 241, 111859.
  76. Suzuki, T.; Miyamoto, K.; Yokoyama, N.; Sugi, M.; Kagioka, A.; Kitao, Y.; Adachi, T.; Ohsawa, M.; Mizukami, H.; Makino, T. Processed aconite root and its active ingredient neoline may alleviate oxaliplatin-induced peripheral neuropathic pain. J. Ethnopharmacol. 2016, 186, 44–52.
  77. Lai, M.C.; Liu, I.-M.; Liou, S.-S.; Chang, Y.-S. Mesaconitine plays the major role in the antinociceptive and anti-inflammatory activities of Radix Aconiti Carmichaeli (Chuan Wu). J. Food Drug Anal. 2011, 19, 362–368.
  78. Shu, H.; Hayashida, M.; Arita, H.; Huang, W.; Xiao, L.; Chiba, S.; Sekiyama, H.; Hanaoka, K. High doses of processed Aconiti tuber inhibit the acute but potentiate the chronic antinociception of morphine. J. Ethnopharmacol. 2008, 119, 276–283.
  79. Zafar, S.; Ahmad, M.A.; Siddiqui, T.A. Acute Toxicity and Antinociceptive Properties of Delphinium denudatum. Pharm. Biol. 2003, 41, 542–545.
  80. Oyama, T.; Isono, T.; Suzuki, Y.; Hayakawa, Y. Anti-nociceptive Effects of Aconiti Tuber and its Alkaloids. Am. J. Chin. Med. 1994, 22, 175–182.
  81. Deng, J.; Han, J.; Chen, J.; Zhang, Y.; Huang, Q.; Wang, Y.; Qi, X.; Liu, Z.; Leung, E.L.-H.; Wang, D. Comparison of analgesic activities of aconitine in different mice pain models. PLoS ONE 2021, 16, e0249276.
  82. Wu, Y.; Shao, S.; Guo, Q.; Xu, C.; Xia, H.; Zhang, T.; Shi, J. Aconicatisulfonines A and B, Analgesic Zwitterionic C20-Diterpenoid Alkaloids with a Rearranged Atisane Skeleton from Aconitum carmichaelii. Org. Lett. 2019, 21, 6850–6854.
  83. Zaheer, I.; Rahman, S.Z.; Khan, R.A.; Parveen, M.; Ahmad, M. Evaluation of analgesic activity of extracts of Delphinium denudatum in animal models: A dose dependent pre-clinical trial. J. Clin. Diagn. Res. 2018, 12, FC01–FC04.
  84. Li, Q.; Sun, S.D.; Wang, M.Y.; Li, C.F.; Yuan, D.; Fu, H.Z. Chemical constituents and analgesic activity of Aconitum kusnezoffii Reichb. J. Chin. Pharm. Sci. 2018, 27, 855–863.
  85. Guo, Q.; Xia, H.; Meng, X.; Shi, G.; Xu, C.; Zhu, C.; Zhang, T.; Shi, J. C19-Diterpenoid alkaloid arabinosides from an aqueous extract of the lateral root of Aconitum carmichaelii and their analgesic activities. Acta Pharm. Sin. B 2018, 8, 409–419.
  86. Nesterova, Y.V.; Povet’yeva, T.; Suslov, N.; Zyuz’kov, G.; Pushkarskii, S.; Aksinenko, S.; Schultz, E.; Kravtsova, S.; Krapivin, A. Analgesic Activity of Diterpene Alkaloids from Aconitum baikalensis. Bull. Exp. Biol. Med. 2014, 157, 488–491.
  87. Zhao, D.-K.; Ai, H.-L.; Zi, S.-H.; Zhang, L.-M.; Yang, S.-C.; Guo, H.-C.; Shen, Y.; Chen, Y.-P.; Chen, J.-J. Four new C 18 -diterpenoid alkaloids with analgesic activity from Aconitum weixiense. Fitoterapia 2013, 91, 280–283.
  88. Wang, D.-P.; Lou, H.-Y.; Huang, L.; Hao, X.-J.; Liang, G.-Y.; Yang, Z.-C.; Pan, W.-D. A novel franchetine type norditerpenoid isolated from the roots of Aconitum carmichaeli Debx. with potential analgesic activity and less toxicity. Bioorganic Med. Chem. Lett. 2012, 22, 4444–4446.
  89. Taki, M.; Niitu, K.; Omiya, Y.; Noguchi, M.; Fukuchi, M.; Aburada, M.; Okada, M. 8-O-Cinnamoylneoline, a New Alkaloid from the Flower Buds of Aconitum carmichaeli and its Toxic and Analgesic Activities. Planta Med. 2003, 69, 800–803.
  90. Song, M.-K.; Liu, H.; Jiang, H.-L.; Yue, J.-M.; Hu, G.-Y.; Chen, H.-Z. Discovery of talatisamine as a novel specific blocker for the delayed rectifier K+ channels in rat hippocampal neurons. Neuroscience 2008, 155, 469–475.
  91. Liu, H.; Li, Y.; Song, M.; Tan, X.; Cheng, F.; Zheng, S.; Shen, J.; Luo, X.; Ji, R.; Yue, J. Structure-Based Discovery of Potassium Channel Blockers from Natural Products: Virtual Screening and Electrophysiological Assay Testing. Chem. Biol. 2003, 10, 1103–1113.
  92. Zheng, X.L.; Xie, Z.H.; Zhu, Z.Y.; Liu, Z.; Wang, Y.; Wei, L.F.; Yang, H.; Yang, H.N.; Liu, Y.Q.; Bi, J.Z. Methyllycaconitine Alleviates Amyloid-β Peptides-Induced Cytotoxicity in SH-SY5Y Cells. PLoS ONE 2014, 9, e111536.
  93. Wan, L.X.; Zhang, J.F.; Zhen, Y.Q.; Zhang, L.; Li, X.; Gao, F.; Zhou, X.L. Isolation, Structure Elucidation, Semi-Synthesis, and Structural Modification of C19-Diterpenoid Alkaloids from Aconitum apetalumand Their Neuroprotective Activities. J. Nat. Prod. 2021, 84, 1067–1077.
  94. Nesterova, Y.V.; Povet’eva, T.N.; Suslov, N.I.; Zyuz’kov, G.N.; Zhdanov, V.V.; Fedorova, Y.S.; Kul’pin, P.V.; Shaposhnikov, K.V. Correction of Cholinergic Abnormalities in Mnestic Processes with Diterpene Alkaloid Songorine. Bull. Exp. Biol. Med. 2018, 165, 10–13.
  95. Zyuz’kov, G.N.; Suslov, N.I.; Losev, E.A.; Ermolaeva, L.A.; Zhdanov, V.V.; Udut, E.V.; Miroshnichenko, L.A.; Simanina, E.V.; Demkin, V.P.; Povet’eva, T.N. Cerebroprotective and Regenerative Effects of Alkaloid Z77 under Conditions of Brain Ischemia. Bull. Exp. Biol. Med. 2015, 158, 352–355.
  96. Huang, S.; Zhang, J.-F.; Chen, L.; Gao, F.; Zhou, X.-L. Diterpenoid alkaloids from Aconitum anthoroideum that offer protection against MPP+–Induced apoptosis of SH–SY5Y cells and acetylcholinesterase inhibitory activity. Phytochemistry 2020, 178, 112459.
  97. Wang, Y.; Zhang, H.; Wang, J.; Yu, M.; Zhang, Q.; Yan, S.; You, D.; Shi, L.; Zhang, L.; Wang, L.; et al. Aconiti lateralis Radix Praeparata inhibits Alzheimer’s disease by regulating the complex regulation network with the core of GRIN1 and MAPK1. Pharm. Biol. 2021, 59, 311–320.
  98. Luo, Z.-H.; Chen, Y.; Sun, X.-Y.; Fan, H.; Li, W.; Deng, L.; Yin, T.-P. A new diterpenoid alkaloid from Aconitum hemsleyanum. Nat. Prod. Res. 2020, 34, 1331–1336.
  99. Jiang, G.-Y.; Qin, L.-L.; Gao, F.; Huang, S.; Zhou, X.-L. Fifteen new diterpenoid alkaloids from the roots of Aconitum kirinense Nakai. Fitoterapia 2020, 141, 104477.
  100. Ahmad, H.; Ahmad, S.; Shah, S.A.A.; Khan, H.U.; Khan, F.A.; Ali, M.; Latif, A.; Shaheen, F.; Ahmad, M. Selective dual cholinesterase inhibitors from Aconitum laeve. J. Asian Nat. Prod. Res. 2018, 20, 172–181.
  101. Ahmad, H.; Ahmad, S.; Ali, M.; Latif, A.; Shah, S.A.A.; Naz, H.; Rahman, N.U.; Shaheen, F.; Wadood, A.; Khan, H.U.; et al. Norditerpenoid alkaloids of Delphinium denudatum as cholinesterase inhibitors. Bioorganic Chem. 2018, 78, 427–435.
  102. Ahmad, H.; Ahmad, S.; Shah, S.A.A.; Latif, A.; Ali, M.; Khan, F.A.; Tahir, M.N.; Shaheen, F.; Wadood, A.; Ahmad, M. Antioxidant and anticholinesterase potential of diterpenoid alkaloids from Aconitum heterophyllum. Bioorganic Med. Chem. 2017, 25, 3368–3376.
  103. Ahmad, H.; Ahmad, S.; Khan, E.; Shahzad, A.; Ali, M.; Tahir, M.N.; Shaheen, F.; Ahmad, M. Isolation, crystal structure determination and cholinesterase inhibitory potential of isotalatizidine hydrate from Delphinium denudatum. Pharm. Biol. 2017, 55, 680–686.
  104. Nisar, M.; Obaidullah; Ahmad, M.; Wadood, N.; Lodhi, M.A.; Shaheen, F.; Choudhary, M.I. New diterpenoid alkaloids from Aconitum heterophyllum Wall: Selective butyrylcholinestrase inhibitors. J. Enzym. Inhib. Med. Chem. 2009, 24, 47–51.
  105. Atta-ur-Rahman; Fatima, N.; Akhtar, F.; Choudhary, M.I.; Khalid, A. New norditerpenoid alkaloids from Aconitum falconeri. J. Nat. Prod. 2000, 63, 1393–1395.
  106. Andreasen, J.T.; Olsen, G.M.; Wiborg, O.; Redrobe, J.P. Antidepressant-like effects of nicotinic acetylcholine receptor antagonists, but not agonists, in the mouse forced swim and mouse tail suspension tests. J. Psychopharmacol. 2009, 23, 797–804.
  107. Nesterova, Y.V.; Povetieva, T.N.; Suslov, N.I.; Semenov, A.A.; Pushkarskiy, S.V. Antidepressant Activity of Diterpene Alkaloids of Aconitum baicalense Turcz. Bull. Exp. Biol. Med. 2011, 151, 425–428.
  108. Liu, L.; Li, B.; Zhou, Y.; Wang, L.; Tang, F.; Shao, D.; Jiang, X.; Zhao, H.; Cui, R.; Li, Y. Antidepressant-like Effect of Fuzi Total Alkaloid on Ovariectomized Mice. J. Pharmacol. Sci. 2012, 120, 280–287.
  109. Mineur, Y.S.; Mose, T.N.; Blakeman, S.; Picciotto, M.R. Hippocampal α7 nicotinic ACh receptors contribute to modulation of depression-like behaviour in C57BL/6J mice. Br. J. Pharmacol. 2018, 175, 1903–1914.
  110. Nesterova, Y.V.; Povet’eva, T.N.; Suslov, N.I.; Shults, E.E.; Ziuz’kov, G.N.; Aksinenko, S.G.; Afanas’eva, O.G.; Krapivin, A.V.; Kharina, T.G. Anxiolytic Activity of Diterpene Alkaloid Songorine. Bull. Exp. Biol. Med. 2015, 159, 620–622.
  111. Ahmad, M.; Yousuf, S.; Khan, M.B.; Ahmad, A.S.; Saleem, S.; Hoda, M.N.; Islam, F. Protective effects of ethanolic extract of Delphinium denudatum in a rat model of Parkinson’s disease. Hum. Exp. Toxicol. 2006, 25, 361–368.
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Subjects: Neurosciences; Chemistry, Medicinal
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Arash Salehi
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Mustafa Ghanadian
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Behzad Zolfaghari
,
Amir Reza Jassbi
,
Maryam Fattahian
,
Parham Reisi
,
Dezső Csupor
,
Ikhlas A. Khan
,
Zulfiqar Ali
,
Mustafa ghanadian
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Update Date: 22 May 2023
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