Doses Of Harmaline Research Articles

Harmaline downregulates angiogenesis markers and suppresses the growth of 4T1 breast cancer cells in vivo and in vitro

The anti-angiogenic effects of harmaline, an alkaloid with emerging anti-tumor properties, are under investigation. In the present study, the effects of different doses of harmaline, either alone or in combination with doxorubicin (DOX), were assessed in mice models of breast tumor. Breast tumors were created by the subcutaneous injection of 4T1 cells into Balb/c mice. The mice received either normal saline, harmaline alone (10, 20, or 30 mg/kg), or harmaline (20 mg/kg) + DOX (10 mg/kg). Immunohistochemistry, ELISA, and real-time PCR were conducted to measure target parameters. Harmaline significantly increased tumor cells’ sensitivity to DOX as confirmed by a significantly reduced tumor volume in the harmaline + DOX group after 24 days (P < 0.05). Also, the levels of Ki‐67 (P < 0.001), MMP-2 (P < 0.001), and VEGF (P < 0.001) significantly decreased while the level of E-cadherin increased (P < 0.001) in the tumor tissues of the mice treated with 20 or 30 mg/kg harmaline or harmaline (20 mg/kg) + DOX (10 mg/kg) compared to the control group. There was a significant reduction in the serum level of IL-4 in tumor-bearing mice treated with harmaline (P < 0.05), and IFN-γ serum level was significantly augmented in all experimental groups compared to the control group (P < 0.05). The genes encoding VEGF, VEGF receptor 2, CD105, and COX2 were significantly down-regulated (P < 0.05 for all) in harmaline-treated (either alone or in combination with DOX) mice. In conclusion, harmaline seems to have the potential to be used as an anticancer agent for treating breast cancer.

Synergistic antidepressant- and anxiolytic-like effects of harmaline along with cinanserin in acute restraint stress-treated mice.

RationaleAcute restraint stress (ARS) is an experimental paradigm used for the induction of rodent models of stress-produced neuropsychiatric disorders, such as depression and anxiety. β-carbolines and serotonin (5-HT) systems are involved in the modulation of depression and anxiety behaviors. ObjectiveThis study was designed to examine the effects of intracerebroventricular (i.c.v.) injection of cinanserin (5-HT2 receptor antagonist) on harmaline-induced responses on depression- and anxiety-like behaviors in the ARS mice.MethodsFor i.c.v. infusion, guide cannula was surgically implanted in the left lateral ventricle of mice. The ARS model was conducted via movement restraint at a period of 4 h. Depression- and anxiety-related behaviors were evaluated by forced swim test (FST) and elevated plus maze (EPM), respectively.ResultsThe results displayed that the ARS mice showed depressive- and anxiety-like responses. I.p. administration of different doses of harmaline (0.31, 0.625 and 1.25 mg/kg) or i.c.v. microinjection of cinanserin (1, 2.5, and 5 μg/mouse) blocked depression- and anxiogenic-like behaviors in the ARS mice. Furthermore, co-administration of harmaline (1.25 mg/kg; i.p.) and cinanserin (5 μg/mouse; i.c.v.) prevented the depression- and anxiogenic-like effects in the ARS mice. We found a synergistic antidepressant- and anxiolytic-like effects of harmaline and cinanserin in the ARS mice.ConclusionsThese results propose an interaction between harmaline and cinanserin to prevent depressive- and anxiogenic-like behaviors in the ARS mice.

Development of Harmaline-induced Tremor in a Swine Model.

BackgroundIn the field of translational neuroscience research, it is critical to utilize a large animal model to test the feasibility, safety, and functionality of novel therapies. Here, we describe a protocol for the development of a large animal model of tremor.MethodsIn a pig model, tremor was induced with harmaline and measured with wireless accelerometers attached to the limbs. Three different doses of harmaline were tested and three repetitive injections were made at 72-hour intervals. To fully characterize the drug-induced tremor, onset time, tremor amplitude, maintained duration, and peak tremor frequency were analyzed.ResultsHarmaline-induced tremor appeared immediately following intravenous injection of harmaline. Tremor was maintained over 2 hours. Its frequency was 10–16 Hz, which was independent of doses. Dose-dependent responses were observed in tremor amplitude, triggering time, and tremor-maintained duration. Repetitive injection of harmaline desensitized the harmaline effect.DiscussionWe provide a detailed protocol for training, drug injection, device selection, and tremor recording optimized to create a swine model of tremor with harmaline. Our protocol provides reliable tremor in pigs and suggests pig as a valid translational large animal model of tremor.

Modification of 5-methoxy-N,N-dimethyltryptamine-induced hyperactivity by monoamine oxidase A inhibitor harmaline in mice and the underlying serotonergic mechanisms.

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and harmaline are indolealkylamine (IAA) drugs often abused together. Our recent studies have revealed the significant effects of co-administered harmaline, a monoamine oxidase inhibitor (MAOI), on 5-MeO-DMT pharmacokinetics and thermoregulation. This study was to delineate the impact of harmaline and 5-MeO-DMT on home-cage activity in mouse models, as well as the contribution of serotonin (5-HT) receptors. Home-cage activities of individual animals were monitored automatically in the home cages following implantation of telemetry transmitters and administration of various doses of IAA drugs and 5-HT receptor antagonists. Area under the effect curve (AUEC) of mouse activity values were calculated by trapezoidal rule. High dose of harmaline (15mg/kg, ip) alone caused an early-phase (0-45min) hypoactivity in mice that was fully attenuated by 5-HT1A receptor antagonist WAY-100635, whereas a late-phase (45-180min) hyperactivity that was reduced by 5-HT2A receptor antagonist MDL-100907. 5-MeO-DMT (10 and 20mg/kg, ip) alone induced biphasic effects, an early-phase (0-45min) hypoactivity that was completely attenuated by WAY-100635, and a late-phase (45-180min) hyperactivity that was fully suppressed by MDL-100907. Interestingly, co-administration of MAOI harmaline (2-15mg/kg) with a subthreshold dose of 5-MeO-DMT (2mg/kg) induced excessive hyperactivities at late phase (45-180min) that could be abolished by either WAY-100635 or MDL-100907. Co-administration of MAOI with 5-MeO-DMT provokes excessive late-phase hyperactivity, which involves the activation of both 5-HT1A and 5-HT2A receptors.

Harmaline-induced amnesia: Possible role of the amygdala dopaminergic system

In this study, we examined the effect of bilateral intra-basolateral amygdala (intra-BLA) microinjections of dopamine receptor agents on amnesia induced by a β-carboline alkaloid, harmaline in mice. We used a step-down method to assess memory and then, hole-board method to assess exploratory behaviors. The results showed that pre-training intra-BLA injections of dopamine D1 receptor antagonist and agonist (SCH23390 (0.5μg/mouse) and SKF38393 (0.5μg/mouse), respectively) impaired memory acquisition. In contrast, pre-training intra-BLA injections of dopamine D2 receptor antagonist and agonist (sulpiride and quinpirole, respectively) have no significant effect on memory acquisition. Pre-training intra-peritoneal (i.p.) injection of harmaline (1mg/kg) decreased memory acquisition. However, co-administration of SCH 23390 (0.01μg/mouse) with different doses of harmaline did not alter amnesia. Conversely, pre-training intra-BLA injection of SKF38393 (0.1μg/mouse), sulpiride (0.25μg/mouse) or quinpirole (0.1μg/mouse) reversed harmaline (1mg/kg, i.p.)-induced amnesia. Furthermore, all above doses of drugs had no effect on locomotor activity. In conclusion, the dopamine D1 and D2 receptors of the BLA may be involved in the impairment of memory acquisition induced by harmaline.

Cerebellar output regulation by the climbing and mossy fibers with and without the inferior olive.

The activity of the olivocerebellar complex and the structures related in series with it have been studied using the complementary action of harmaline and 3-acetylpyridine to isolate the two principal inputs to the cerebellar Purkinje cells. The activities of the various nuclei as well as the entire brain have been simultaneously monitored using the [14C]2-deoxy-glucose method under the various combined effects of the pharmacological agents. (1) Tremogenic doses of harmaline increased the frequency of discharge in selected parts of the olivocerebellar system, increasing climbing fiber input and reducing Purkinje cell simple spike discharges in corresponding parts of the cerebellar cortex. The metabolic activity increased in the inferior olive and in the red nucleus. The results are interpreted as a net reduction of Purkinje cell inhibition on their target neurons, leading to a facilitatory cerebellar output. (2) Systemic injection of neurotoxic doses of 3-acetylpyridine selectively produced total degeneration of the neurons in the inferior olive, resulting in the suppression of complex spikes and a net increase in simple spike output from the Purkinje cells. The metabolic consequences were a reduction or absence in the inferior olive, decrease in the red nucleus, and increases in the Purkinje cell target neuron regions, including the intracerebellar and vestibular nuclei. The study of long survival times following the neurotoxic treatment revealed a transient metabolic marking of the inferior olive during the active glial processes accompanying the degeneration. In other parts the radioautographic changes caused by the destruction of the inferior olive persisted for about 1 month after the administration of the drug. (3) Tremogenic doses of harmaline were given to rats at different times following treatment with 3-acetylpyridine. It was demonstrated that: (a) intoxication of the inferior olive started within the second hour after 3-acetylpyridine administration, corresponding to the time at which the metabolic response to harmaline was also abolished; and (b) the increased metabolic activity produced by harmaline in the olivocerebellar complex was a consequence of an increased activity of the neurons of the inferior olive rather than a direct pharmacological effect of the drug. (4) Partial lesions of the inferior olive led to increased metabolic activity of those parts of the intracerebellar nuclei topographically related to the destroyed parts of the inferior olive. (5) In 3-acetylpyridine-treated animals, local ablation as well as local inactivation of the cerebellar cortex produced localized suppression of the intense labeling in the intracerebellar nuclei obtained in these animals. Since these regions receive synapses which are normally inhibitory, suppression of labeling clearly supports the hypothesis that regional marking may very well be produced by the activity of the presynaptic terminals themselves...