Reserpine

Neuromolecular Med. 2014 Jun;16(2):350-9.

Attenuation of reserpine-induced pain/depression dyad by gentiopicroside through downregulation of GluN2B receptors in the amygdala of mice.[Pubmed: 24584520 ]

Epidemiological studies demonstrate that pain frequently occurs comorbid with depression. Gentiopicroside (Gent) is a secoiridoid compound isolated from Gentiana lutea that exhibits analgesic properties and inhibits the expression of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors in the anterior cingulate cortex of mice. However, the effects of Gent on the Reserpine-induced pain/depression dyad and its underlying mechanisms are unclear.
METHODS AND RESULTS:
Reserpine administration (1 mg/kg subcutaneous daily for 3 days) caused a significant decrease in the nociceptive threshold as evidenced by the reduced paw withdrawal latency in response to a radiant heat source and mechanical allodynia. Behavioral detection indicated a significant increase in immobility time during a forced swim test, as well as decreased time in the central area and total travel distance in an open field test. Furthermore, reserpinized animals exhibited increased oxidative stress. Systemic Gent administration dose-dependently ameliorated the behavioral deficits associated with Reserpine-induced pain/depression dyad. At the same time, the decrease in biogenic amine levels (norepinephrine, dopamine, and serotonin) was integrated with the increase in caspase-3 levels and GluN2B-containing NMDA receptors in the amygdala of the Reserpine-injected mice. Gent significantly reversed the changes in the levels of biogenic amines, caspase-3, and GluN2B-containing NMDA receptors in amygdala. However, Gent did not affect the expression of GluN2A-containing NMDA receptors. The inhibitory effects of Gent on oxidative stress were occluded by simultaneous treatment of GluN2B receptors antagonist Ro25-6981.
CONCLUSIONS:
Our study provides strong evidence that Gent inhibits Reserpine-induced pain/depression dyad by downregulating GluN2B receptors in the amygdala.

Behav Brain Res. 2013 Sep 15;253:68-77.

Cognitive, motor and tyrosine hydroxylase temporal impairment in a model of parkinsonism induced by reserpine.[Pubmed: 23831411]

Studies have suggested that cognitive deficits can precede motor alterations in Parkinson's disease (PD). However, in general, classic animal models are based on severe motor impairment after one single administration of neurotoxins, and thereby do not express the progressive nature of the pathology.
METHODS AND RESULTS:
A previous study showed that the repeated administration with a low dose (0.1mg/kg) of the monoamine depleting agent Reserpine induces a gradual appearance of motor signs of pharmacological parkinsonism in rats. Here, we showed this repeated treatment with Reserpine induced a memory impairment (evaluated by the novel object recognition task) before the gradual appearance of the motor signs. Additionally, these alterations were accompanied by decreased tyrosine hydroxylase (TH) striatal levels and reduced number of TH cells in substantia nigra pars compacta (SNpc). After 30 days without treatment, Reserpine-treated animals showed normal levels of striatal TH, partial recovery of TH cells in SNpc, recovery of motor function, but not reversal of the memory impairment. Furthermore, the motor alterations were statistically correlated with decreased TH levels (GD, CA1, PFC and DS) and number of TH cells (SNpc and VTA) in the brain.
CONCLUSIONS:
Thus, we extended previous results showing that the gradual appearance of motor impairment induced by repeated treatment with a low dose of Reserpine is preceded by short-term memory impairment, as well as accompanied by neurochemical alterations compatible with the pathology of PD.

Exp Gerontol. 2009 Jun-Jul;44(6-7):462-6.

Reserpine ameliorates Abeta toxicity in the Alzheimer's disease model in Caenorhabditis elegans.[Pubmed: 19264117 ]

METHODS AND RESULTS:
Earlier we have reported that Reserpine, an antihypertensive drug, known to downregulate biogenic amines through inhibition of the vesicular monoamine transporter (VMAT), increases longevity of Caenorhabditis elegans with a high quality of life, namely, enhanced and prolonged mobility (Srivastava et al., 2008). As neurodegenerative diseases are of adult onset, we addressed the protective ability of Reserpine against neurodegenerative diseases, especially Alzheimer's disease (AD). In the well established AD model in C. elegans, Amyloid beta (Abeta) is expressed in the muscles and Abeta toxicity is manifested as paralysis (Link, 1995).
CONCLUSIONS:
In this model, Reserpine significantly delayed paralysis and increased the longevity. In addition, Reserpine provided thermotolerance, but interestingly the Abeta transcript and expression levels remains grossly unchanged.

Phytomedicine. 2015 Feb 15;22(2):308-18.

Cytotoxicity of the indole alkaloid reserpine from Rauwolfia serpentina against drug-resistant tumor cells.[Pubmed: 25765838 ]

The antihypertensive Reserpine is an indole alkaloid from Rauwolfia serpentina and exerts also profound activity against cancer cells in vitro and in vivo. The present investigation was undertaken to investigate possible modes of action to explain its activity toward drug-resistant tumor cells.
METHODS AND RESULTS:
Sensitive and drug-resistant tumor cell lines overexpressing P-glycoprotein (ABCB1/MDR1), breast cancer resistance protein (ABCG2/BCRP), mutation-activated epidermal growth factor receptor (EGFR), wild-type and p53-knockout cells as well as the NCI panel of cell lines from different tumor origin were analyzed. Reserpine's cytotoxicity was investigated by resazurin and sulforhodamine assays, flow cytometry, and COMPARE and hierarchical cluster analyses of transcriptome-wide microarray-based RNA expressions. P-glycoprotein- or BCRP overexpressing tumor cells did not reveal cross-resistance to Reserpine. EGFR-overexpressing cells were collateral sensitive and p53- Knockout cells cross-resistant to this drug compared to their wild-type parental cell lines. Reserpine increased the uptake of doxorubicin in P-glycoprotein-overexpressing cells, indicating that Reserpine inhibited the efflux function of P-glycoprotein. Using molecular docking, we found that Reserpine bound with even higher binding energy to P-glycoprotein and EGFR than the control drugs verapamil (P-glycoprotein inhibitor) and erlotinib (EGFR inhibitor). COMPARE and cluster analyses of microarray data showed that the mRNA expression of a panel of genes predicted the sensitivity or resistance of the NCI tumor cell line panel with statistical significance. The genes belonged to diverse pathways and biological functions, e.g. cell survival and apoptosis, EGFR activation, regulation of angiogenesis, cell mobility, cell adhesion, immunological functions, mTOR signaling, and Wnt signaling.
CONCLUSIONS:
The lack of cross-resistance to most resistance mechanisms and the collateral sensitivity in EGFR-transfectants compared to wild-type cells speak for a promising role of Reserpine in cancer chemotherapy. Reserpine deserves further consideration for cancer therapy in the clinical setting.

Neurochem Int. 2013 Oct;63(4):316-21.

Protective effect of nebivolol on reserpine-induced neurobehavioral and biochemical alterations in rats.[Pubmed: 23871717]

Reserpine-induced orofacial dyskinesia is a model that shares some mechanists' aspects with tardive dyskinesia whose pathophysiology has been related to oxidative stress.
METHODS AND RESULTS:
The present study was aimed to explore neuroprotective effects of nebivolol, an antihypertensive agent, on Reserpine-induced neurobehavioral and biochemical alterations in rats. Reserpine (1mg/kg, s.c.) was used to induce neurotoxicity. Administration of Reserpine for 3 days every other day significantly increased the vacuous chewing movements (VCMs), tongue protrusions (TPs) and reduced the locomotor activity in rats. Pre-treatment with nebivolol (5 and 10mg/kg, p.o. for 5 days) showed dose dependant decrease in VCMs and TP induced by Reserpine. Nebivolol also showed significant improvement in locomotor activity. Reserpine significantly increased lipid peroxidation and reduced the levels of defensive antioxidant enzymes like catalase (CAT), superoxide dismutase (SOD) and reduced glutathione (GSH) in rat brain. Nebivolol reversed these effects of Reserpine on oxidative stress indices; indicating amelioration of oxidative stress in rat brains.
CONCLUSIONS:
The results of the present study indicated that nebivolol has a protective role against Reserpine-induced orofacial dyskinesia. Thus, the use of nebivolol as a therapeutic agent for the treatment of tardive dyskinesia may be considered.