Anethole is a terpenoid with antioxidant, anti-inflammatory, and neuronal blockade effects, and the present work was undertaken to study the neuroprotective activity of anethole against diabetes mellitus (DM)-induced neuropathy. Streptozotocin-induced DM rats were used to investigate the effects of anethole treatment on morphological, electrophysiological, and biochemical alterations of the sciatic nerve (SN). Anethole partially prevented the mechanical hyposensitivity caused by DM and fully prevented the DM-induced decrease in the cross-sectional area of the SN. In relation to electrophysiological properties of SN fibers, DM reduced the frequency of occurrence of the 3rd component of the compound action potential (CAP) by 15%. It also significantly reduced the conduction velocity of the 1st and 2nd CAP components from 104.6 ± 3.47 and 39.8 ± 1.02 to 89.9 ± 3.03 and 35.4 ± 1.56 m/s, respectively, and increased the duration of the 2nd CAP component from 0.66 ± 0.04 to 0.82 ± 0.09 ms. DM also increases oxidative stress in the SN, altering values related to thiol, TBARS, SOD, and CAT activities. Anethole was capable of fully preventing all these DM electrophysiological and biochemical alterations in the nerve. Thus, the magnitude of the DM-induced neural effects seen in this work, and the prevention afforded by anethole treatment, place this compound in a very favorable position as a potential therapeutic agent for treating diabetic peripheral neuropathy.

Background: Hyptis crenata is a plant of great ethnopharmacological importance widely distributed in South American countries. In Northeast Brazil, teas or infusions of its aerial parts are used in folk medicine to treat several acute and chronic inflammatory diseases. In a previous work we have demonstrated that the essential oil of H. crenata (EOHc) has an antiedematogenic effect. The aim of this work was to evaluate the effect of EOHc on cytokines secretion and cellular infiltration. Methods: Peritonitis and paw edema models induced by carrageenan were used to determine leucocyte count, myeloperoxidase (MPO) activity, nitrite, and cytokines secretion. Results: EOHc (10–300 mg/kg) significantly inhibited leucocyte migration and reduced the neutrophil count (control: 1.46 × 10³ ± 0.031 × 10³/mL) of the total leucocytes population in extracellular exudate (control: 2.14 × 10³ ± 0.149 × 10³/mL) by 15.00%, 43.29%, 65.52%, and 72.83% for the doses of 10, 30, 100, and 300 mg/kg EOHc, respectively (EC₅₀: 24.15 mg/kg). EOHc (100 mg/kg) inhibited the increase in myeloperoxidase activity and completely blocked the increase in nitrite concentration induced by carrageenan. EOHc markedly reduced the pro-inflammatory cytokines (IL-6, MCP-1, IFN-γ, TNF-α, and IL-12p70) and increased IL-10, an anti-inflammatory cytokine (compared to control group, p < 0.05). Conclusions: This study demonstrates that EOHc has a long-lasting anti-inflammatory effect mediated through interference on MPO activity, and nitrite, and cytokines secretion. This effect, coupled with low EOHc toxicity, as far as results obtained in mice could be translated to humans, suggests that EOHc has great potentiality as a therapeutic agent.

Background/Objectives: Anethole, a terpenoid with several pharmacologic effects, is the major constituent of the essential oil of Croton zehntneri (EOCz), Pax & K. Hoffm, Euphorbiaceae. Due to the mild renal toxicity associated with high doses of EOCz, its potential therapeutic effects on several diseases, and the fact that its chemical composition consists of 80% anethole, the renal effects of anethole in mice were investigated. Methods: Mice were randomly divided into eight groups, dosed daily as follows: Group 1—CTRL (control; vehicle only); Groups 2—A100, 3—A125_2x, and 4—A250 (dosed with 100, 125 twice daily, and 250 mg/kg, per os anethole); Group 5—_SUBAKI (i.p. albumin to induce hyperproteinemia and proteinuria; subclinical acute kidney injury); and Groups 6—_SUBAKI+A100, 7—_SUBAKI+A125_2x, and 8—_SUBAKI+A250 (per os anethole + i.p. albumin). Results: The A125_2x and A250 groups significantly increased urinary proteinuria and interstitial inflammation (p < 0.001, for these groups). _SUBAKI+A100, _SUBAKI+A125_2x, and _SUBAKI+A250 showed a neither protective nor additive effect in the proteinuria induced by anethole and by administered albumin. The anethole-induced proteinuria was spontaneously reversible in approximately 4 weeks. In vitro experiments showed that anethole (300 µg/mL) inhibits albumin uptake from the culture medium by tubular cells. Conclusions: Anethole at high doses bears renal acute toxicity that, although mild and spontaneously fully reversible, must be taken into consideration in a cost–benefit analysis.

A previous investigation on limonene (LM), perillyl alcohol (POH), and carveol (CV), focused on the structure–activity relationship and hydroxyl group, documented that the presence of the hydroxyl group influences the pharmacodynamic potency of these agents, inhibiting smooth muscle contraction with the order of potency: POH > CV > LM. That investigation also suggested a mechanism of action, which importantly included activity on the voltage-dependent calcium channel. Here, we investigated whether this structure–activity relationship also applies to nerve excitability (an activity greatly dependent on sodium channels) using compound action potential (CAP) recordings from mouse sciatic nerves and in silico simulations. POH, CV, and LM inhibited both the positive amplitudes and conduction velocities of the two CAP components in a concentration-dependent manner, with IC₅₀ values of 0.8, 1.0, and 4.3 mM (1st component) and 0.6, 0.6, and 3.0 mM (2nd component) for amplitude, and 2.4, 2.4, and 7.1 mM (1st component) and 1.0, 2.6, and 4.3 mM (2nd component) for conduction velocity. The order of pharmacodynamic potency, thus, was POH = CV > LM. In silico simulation demonstrated that POH and CV penetrate the Nav 1.6 and accommodate in the channel at the interface between the selectivity filter and the central cavity, a position very favorable to block the channel pore. In contrast, LM exhibited a markedly different docking profile, suggesting that LM binding is less likely to directly obstruct sodium permeation. In conclusion, the three substances investigated inhibited nerve excitability, but those with a hydroxyl group demonstrated greater pharmacodynamic potency.