Reza Rahimian

Medicinal Chemistry of Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors

Nicotinamide phoshophoribosyltransferase (NAMPT) plays a key role in the replenishment of the NAD pool in cells. This in turn makes this enzyme an important player in bioenergetics and in the regulation of NAD-using enzymes, such as PARPs and sirtuins. Furthermore, there is now ample evidence that NAMPT is secreted and has a role as a cytokine. An important role of either the intracellular or extracellular form of NAMPT has been shown in cancer, inflammation, and metabolic diseases. The first NAMPT inhibitors (FK866 and CHS828) have already entered clinical trials, and a surge in interest in the synthesis of novel molecules has occurred. The present review summarizes the recent progress in this field.

Anti-inflammatory effects of 5-HT3 receptor antagonist, tropisetron on experimental colitis in rats

Background  There is a pressing need for research that will lead to the development of new therapeutic approaches for treating inflammatory bowel disease (IBD). The aim of this study was to investigate the effects of tropisetron, a 5‐Hydroxytryptamine (5‐HT)‐3 receptor antagonist with anti‐inflammatory properties in a model of experimental colitis in rat.

WIN55212-2 attenuates amyloid-beta-induced neuroinflammation in rats through activation of cannabinoid receptors and PPAR-γ pathway

Cannabinoids have been shown to exert neuroprotective effects in a plethora of neurodegenerative conditions. Over the past decade, some studies demonstrate that cannabinoids can interact with nuclear peroxisome proliferator-activated receptors (PPARs). We investigated protective properties of WIN55212-2 (WIN, a non-selective cannabinoid receptor agonist) in beta-amyloid (Aβ)-induced neurodegeneration in rat hippocampus and possible involvement of PPAR-gamma (PPAR-γ). Aβ (1-42) was injected into the hippocampus of male rats. Animals were administered by intracerebroventricular rout the following treatments on days 1, 3, 5, 7: vehicle, WIN, GW9662 (selective PPAR-γ antagonist) plus WIN, AM251 (selective CB₁ receptor antagonist) plus WIN, SR144528 (selective CB₂ receptor antagonist) plus WIN, each of antagonists alone. Injection of Aβ-induced spatial memory impairment and a dramatic rise in hippocampal TNF-α, active caspase 3, nuclear NF-kB levels and TUNEL-positive neurons. WIN administration significantly improved memory function and diminished the elevated levels of these markers, while antagonizing either CB₁ or CB₂ receptor subtype partially attenuated the protective effects. Intriguingly, WIN significantly increased PPAR-γ level and transcriptional activity, the latter being partially inhibited with AM251 but not with SR144528. The enhancing effect on PPAR-γ pathway was crucial to WIN-induced neuroprotection since GW9662 partially reversed the beneficial actions of WIN. Co-administration of the three antagonists led to the complete abrogation of WIN effects. Our findings indicate that WIN exerts neuroprotective and anti-inflammatory actions against Aβ damage through both CB₁ and CB₂ receptors. Of great note, both direct and CB₁-mediated increase in PPAR-γ signaling also contributes to WIN-induced neuroprotection.

The role of serotonin in memory: interactions with neurotransmitters and downstream signaling

Abstract Serotonin, or 5-hydroxytryptamine (5-HT), is found to be involved in many physiological or pathophysiological processes including cognitive function. Seven distinct receptors (5-HT1–7), each with several subpopulations, have been identified for serotonin, which are different in terms of localization and downstream signaling. Because of the development of selective agonists and antagonists for these receptors as well as transgenic animal models of cognitive disorders, our understanding of the role of serotonergic transmission in learning and memory has improved in recent years. A large body of evidence indicates the interplay between serotonergic transmission and other neurotransmitters including acetylcholine, dopamine, γ-aminobutyric acid (GABA) and glutamate, in the neurobiological control of learning and memory. In addition, there has been an alteration in the density of serotonergic receptors in aging and Alzheimer’s disease, and serotonin modulators are found to alter the process of amyloidogenesis and exert cognitive-enhancing properties. Here, we discuss the serotonin-induced modulation of various systems involved in mnesic function including cholinergic, dopaminergic, GABAergic, glutamatergic transmissions as well as amyloidogenesis and intracellular pathways.

Suppression of nitric oxide synthesis by L-NAME reverses the beneficial effects of pioglitazone on scopolamine-induced memory impairment in mice.

UNLABELLED Pioglitazone, an agonist of peroxisome proliferator-activated receptor gamma (PPARγ), which is widely used in treatment of type 2 diabetes, has shown some therapeutic effect in Alzheimers disease. In this study, effects of acute pioglitazone on acquisition, consolidation and retrieval of memory, and also the involvement of nitric oxide (NO) in the effects of pioglitazone on spatial recognition memory has been investigated in a two-trial recognition Y-maze test and passive avoidance in mice. Memory impairment was induced by scopolamine (1mg/kg, i.p.). Pioglitazone (10 and 20mg/kg, p.o.) was administrated prior to either acquisition, consolidation or retention trials, while L-NAME (N-nitro-l-arginine methyl ester), a non-specific NO synthase inhibitor, was administered (10mg/kg, i.p.) 30min before each trial. RESULTS 1) pioglitazone improved the acquisition of recognition spatial memory-impaired by scopolamine; L-NAME dramatically reversed improving effects of pioglitazone on memory acquisition; 2) pioglitazone did not change the consolidation of spatial memory, impaired by scopolamine; 3) pioglitazone improved the retrieval of spatial memory and L-NAME did not alter the beneficial effect of pioglitazone; 4) pioglitazone did not affect scopolamine-induced cognitive impairments in the passive avoidance test. The present study demonstrates the beneficial effect of acute pioglitazone administration on acquisition and retrieval of scopolamine-induced cognitive deficits. This effect was reversed only in acquisition phase by nitric oxide synthase inhibitor, L-NAME, therefore, it could be concluded that NO might be involved in the pioglitazone beneficial effect of spatial memory acquisition.

Involvement of nitric oxide-cGMP pathway in the anticonvulsant effects of lithium chloride on PTZ-induced seizure in mice

Lithium is still the mainstay in the treatment of affective disorders as a mood stabilizer. Lithium also shows some anticonvulsant properties. While the underlying mechanisms of action of lithium are not yet exactly understood, we used a model of clonic seizure induced by pentylenetetrazole (PTZ) in male NMRI mice to investigate whether the anticonvulsant effect of lithium is mediated via NO-cGMP pathway. Injection of a single effective dose of lithium chloride (25 mg/kg) intraperitoneally (i.p.) increased significantly the seizure threshold (P<0.01). The anticonvulsant properties of the effective dose of lithium were prevented by pre-treatment with the per se non-effective doses of L-ARG [the substrate for nitric oxide synthase; NOS] (30 and 50 mg/kg) or sildenafil [a phosphodiesterase 5 inhibitor] (10 and 20 mg/kg). L-NAME [a non-specific NOS inhibitor] (5, 15 and 30 mg/kg), 7-NI [a specific neural NOS inhibitor] (30 and 60 mg/kg) or MB [a guanylyl cyclase inhibitor] (0.5 and 1 mg/kg) augmented the anticonvulsant effect of a sub-effective dose of lithium (10 mg/kg, i.p.). Whereas several doses of aminoguanidine [an inducible NOS inhibitor] (20, 50 and 100 mg/kg) failed to alter the anticonvulsant effect of lithium. Our findings demonstrated that nitric oxide-cyclic GMP pathway could be involved in the anticonvulsant properties of the lithium chloride. In addition, the role of constitutive NOS versus inducible NOS is prominent in this phenomenon.

Granisetron ameliorates acetic acid-induced colitis in rats

Inflammatory bowel disease (IBD) is a chronically relapsing inflammation of the gastrointestinal tract, of which the definite etiology remains ambiguous. Considering the adverse effects and incomplete efficacy of currently administered drugs, it is indispensable to explore new candidates with more desirable therapeutic profiles. 5-HT 3 receptor antagonists have shown analgesic and anti-inflammatory properties in vitro and in vivo. This study aims to investigate granisetron, a 5-HT 3 receptor antagonist, in acetic acid-induced rat colitis and probable involvement of 5-HT3 receptors. Colitis was rendered by instillation of 1 mL of 4% acetic acid (vol/vol) and after 1 hour, granisetron (2 mg/kg), dexamethasone (1 mg/kg), meta-chlorophenylbiguanide (mCPBG, 5 mg/kg), a 5-HT 3 receptor agonist, or granisetron + mCPBG was given intraperitoneally. Twenty-four hours following colitis induction, animals were sacrificed and distal colons were assessed macroscopically, histologically and biochemically (malondialdehyde, myeloperoxidase, tumor necrosis factor-alpha, interleukin-1 beta and interleukin-6). Granisetron or dexamethasone significantly (p < .05) improved macroscopic and histologic scores, curtailed myeloperoxidase activity and diminished colonic levels of inflammatory cytokines and malondialdehyde. The protective effects of granisetron were reversed by concurrent administration of mCPBG. Our data suggests that the salutary effects of granisetron in acetic acid colitis could be mediated by 5-HT3 receptors.

On the benefits of silymarin in murine colitis by improving balance of destructive cytokines and reduction of toxic stress in the bowel cells

Inflammatory bowel disease (IBD) is a multifactorial disease with an unknown etiology characterized by oxidative stress, leucocyte infiltration and a rise in inflammatory cytokines. In this study, we have investigated the effects of silymarin, a mixture of several flavonolignans with established antioxidant and anti-inflammatory properties, on trinitrobenzene sulphonic acid (TNBS)-induced colitis in rats. Experimental colitis was induced in male Wistar-albino rats by delivering TNBS to the distal colon. All the medicines were administered by gavage for seven days. Thirty-six male rats were divided into six groups containing six rats in each one. Control rats received only TNBS. In the treated groups, animals were given different doses of silymarin (40, 80, and 160 mg/kg). Dexamethasone (1 mg/kg) was used as the positive treatment. Colonic status was investigated seven days post induction of colitis through macroscopic, histological, and biochemical analyses. Amelioration of the morphological signs including macroscopic damage, necrotic area, and histology were seen subsequent to treating animals with silymarin. These observations were accompanied by a significant reduction in the degree of both neutrophil infiltration, indicated by decreased myeloperoxidase activity, and lipid peroxidation, as measured by a decline in malodialdehyde content in inflamed colon as well as a decrease in levels of inflammatory cytokines (TNF-α and IL-1β). The results of the present study reveal that the beneficial effect of silymarin in bowel cells is mediated through its anti-oxidant and anti-inflammatory potentials.

Tropisetron ameliorates ischemic brain injury in an embolic model of stroke.

Tropisetron is widely used to counteract chemotherapy-induced emesis. Evidence obtained from human and animal studies shows that tropisetron possesses anti-inflammatory properties. In this study, we assessed the effect of tropisetron on brain damage in a rat thromboembolic model of stroke. Stroke was rendered in rats by introduction of an autologous clot into the middle cerebral artery (MCA). Tropisetron (1 or 3mg/kg); m-chlorophenylbiguanide (mCPBG), a selective 5-HT(3) receptor agonist (15 mg/kg); tropisetron (3mg/kg) plus mCPBG (15 mg/kg); granisetron (3mg/kg); tacrolimus (1mg/kg); or tacrolimus (1mg/kg) plus tropisetron (3mg/kg) were administered intraperitoneally 1h prior to embolization. Behavioral scores and infarct volume as well as myeloperoxidase (MPO) activity and tumor necrosis factor-alpha (TNF-α) level were determined in the ipsilateral cortex 4h and 48 h following stroke induction. Forty-eight hours after embolization, tropisetron (1 or 3mg/kg), tropisetron (3mg/kg) plus mCPBG (15 mg/kg), tacrolimus (1mg/kg), or tacrolimus (1mg/kg) plus tropisetron (3mg/kg) significantly curtailed brain infarction, improved behavioral scores, diminished elevated tissue MPO activity, and reduced TNF-α levels compared to control group (n=6; P<0.05). mCPBG or granisetron had no effect on the mentioned parameters. Tropisetron attenuates brain damage after a thromboembolic event. Beneficial effects of tropisetron in this setting are receptor independent.

Adenosine A2A receptors and uric acid mediate protective effects of inosine against TNBS-induced colitis in rats

Inflammatory bowel disease comprises chronic recurrent inflammation of gastrointestinal tract. This study was conducted to investigate inosine, a potent immunomodulator, in 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced chronic model of experimental colitis, and contribution of adenosine A(2A) receptors and the metabolite uric acid as possible underlying mechanisms. Experimental colitis was rendered in rats by a single colonic administration of 10 mg of TNBS. Inosine, potassium oxonate (a hepatic uricase inhibitor), SCH-442416 (a selective adenosine A(2A) receptor antagonist), inosine+potassium oxonate, or inosine+SCH-442416 were given twice daily for 7 successive days. At the end of experiment, macroscopic and histopathologic scores, colonic malondialdehyde (MDA), Tumor Necrosis Factor-alpha (TNF-α) and Interleukin-1beta (IL-1β) levels, and myeloperoxidase (MPO) activity were assessed. Plasma uric acid level was measured throughout the experiment. Both macroscopic and histological features of colonic injury were markedly ameliorated by either inosine, oxonate or inosine+oxonate. Likewise, the elevated amounts of MPO and MDA abated as well as those of TNF-α and IL-1β (P<0.05). SCH-442416 partially reversed the effect of inosine on theses markers, while inosine+oxonate showed a higher degree of protection than each treatment alone (P<.0.05). No significant difference was observed between TNBS and SCH-442416 groups. Uric acid levels were significantly higher in inosine or oxonate groups compared to control. Inosine+oxonate resulted in an even more elvelated uric acid level than each treatment alone (P<0.05). Inosine elicits notable anti-inflammatory effects on TNBS-induced colitis in rats. Uric acid and adenosine A(2A) receptors contribute to these salutary properties.