Anti-inflammatory Effects Of Thalidomide Research Articles

Thalidomide Attenuates Epileptogenesis and Seizures by Decreasing Brain Inflammation in Lithium Pilocarpine Rat Model.

Thalidomide (TAL) has shown potential therapeutic effects in neurological diseases like epilepsy. Both clinical and preclinical studies show that TAL may act as an antiepileptic drug and as a possible treatment against disease development. However, the evidence for these effects is limited. Therefore, the antiepileptogenic and anti-inflammatory effects of TAL were evaluated herein. Sprague Dawley male rats were randomly allocated to one of five groups (n = 18 per group): control (C); status epilepticus (SE); SE-TAL (25 mg/kg); SE-TAL (50 mg/kg); and SE-topiramate (TOP; 60mg/kg). The lithium-pilocarpine model was used, and one day after SE induction the rats received pharmacological treatment for one week. The brain was obtained, and the hippocampus was micro-dissected 8, 18, and 28 days after SE. TNF-α, IL-6, and IL-1β concentrations were quantified. TOP and TAL (50 mg/kg) increased the latency to the first of many spontaneous recurrent seizures (SRS) and decreased SRS frequency, as well as decreasing TNF-α and IL-1β concentrations in the hippocampus. In conclusion, the results showed that both TAL (50 mg/kg) and TOP have anti-ictogenic and antiepileptogenic effects, possibly by decreasing neuroinflammation.

Thalidomide against Coronavirus Disease 2019 (COVID-19): A Medicine with a Thousand Faces.

Recently, Wuhan, China became the epicenter for the outbreak of novel coronavirus pneumonia (COVID-19). No specific agents are available for treating COVID-19 while some agents such as antivirals, chloroquine, and immunomodulatory agents are under investigation. In vitro and in vivo studies showed that thalidomide impairs the synthesis of tumor necrosis factor alpha (TNF-alpha). It increases peripheral blood CD8+ T cells, plasma interleukin 12 (IL-12) levels, interferon-γ production, and cytotoxic activity. Anti-inflammatory effects of thalidomide on H1N1 influenza virus-induced pulmonary injury in mice showed that thalidomide greatly improves the survival rate, reduces the infiltration of inflammatory cells, cytokine (e.g., IL-6, TNF-α), and chemokine (chemokine ligand 5, C-X-C motif chemokine 10) levels, and inhibits the activated p-NFκB p6. Given the beneficial effects of thalidomide, it is necessary to try it in COVID-19 cases as a therapeutic agent. It is recommended that large clinical trials be designed to find the efficacy and safety of thalidomide in COVID-19.

Anti-apoptotic, anti-oxidant, and anti-inflammatory effects of thalidomide on cerebral ischemia/reperfusion injury in rats

Thalidomide has shown protective effects in different models of ischemia/reperfusion damage. To elucidate the mechanisms of such protection, this study assessed the effects of thalidomide on the oxidative stress and inflammatory response induced by ischemia/reperfusion episodes in rats. Rats underwent middle cerebral artery occlusion (MCAO) for 2hours. All animals were sacrificed after different reperfusion times. Rats were administered either DMSO or thalidomide (20mg/kg (i.p.)) at different times before or during reperfusion: 1) 1h before reperfusion; the infarct area was measured 2h after reperfusion. 2) 10min before reperfusion and 80min after reperfusion; the infarct area was measured 24h after reperfusion; and 3) 10min before reperfusion and 1h, 24h, 48h, and 68h after reperfusion; the infarct area was measured 72h after reperfusion. Thalidomide reduced the infarct area 24h and 72h after MCAO, and decreased the neurological deficit in all groups with respect to controls. Thalidomide also lowered significantly the number of TUNEL-positive cells, levels of Bax, caspase-3, lipoperoxidation, and pro-inflammatory cytokines, and increased the levels of SOD1, Bcl-2 and pAkt. These results show that thalidomide has neuroprotective effects, apparently due to its anti-apoptotic, anti-oxidant, and anti-inflammatory effects.

Anti-inflammatory effect of thalidomide in paraquat-induced pulmonary injury in mice

Thalidomide has been used in inflammatory and autoimmune disorders due to its anti-inflammatory activity. Paraquat (PQ) poisoning causes severe lung injury. PQ-induced pulmonary inflammation and fibrosis are due to its ability to induce oxidative stress, inflammatory and fibrotic reactions. This study was designed to evaluate the anti-inflammatory and anti-fibrotic effect of thalidomide on PQ-induced lung damage in a mouse model. Mice were injected with a single dose of PQ (20mg/kg, i.p.), and treated with thalidomide (25 and 50mg/kg/day, i.p.) for six days. Lung tissues were dissected six days after PQ injection. The results showed that thalidomide ameliorated the biochemical and histological lung alterations induced by PQ. Thalidomide decreased production of inflammatory and fibrogenic cytokine tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and transforming growth factor (TGF)-β1. In addition thalidomide reduced myeloperoxidase (MPO), nitric oxide (NO), and hydroxyproline content in lung tissue. Taken together, the results of this study suggest that thalidomide might be a valuable therapeutic drug in preventing the progression of PQ-induced pulmonary injury.

Anti-inflammatory effect of thalidomide alone or in combination with augmentin in Klebsiella pneumoniae B5055 induced acute lung infection in BALB/c mice

Thalidomide (α-naphtylimidoglutarimide), a psychoactive drug that readily crosses blood-brain barrier, has been shown to exhibit anti-inflammatory, anti-angiogenic, immunomodulatory properties through a mechanism that is not fully established. Keeping these properties in mind, we tried to find out the anti-inflammatory properties of thalidomide in mouse model of acute inflammation by introducing K. pneumoniae B5055 in BALB/c mice via intranasal route. The intranasal instillation of bacteria in this mouse model of acute pneumonia induced inflammation accompanied with significant increase in neutrophil infiltration in the lungs and also increased production of mediators of inflammation (i.e. malondialdehyde, myeloperoxidase and nitric oxide) in the lung tissue. The animals, which received thalidomide alone orally or in combination with augmentin, 30 min prior to bacterial instillation into the lungs via intranasal route, showed significant ( P < 0.05) decrease in neutrophil influx into the lungs and there was significant ( P < 0.05) decrease in the production of malondialdehyde, nitric oxide and myeloperoxidase activity. But the augmentin treatment alone did not decrease the malondialdehyde, myeloperoxidase and nitric oxide significantly ( P > 0.05) as compared to the control group. We therefore conclude that thalidomide ameliorates lung inflammation induced by K. pneumoniae B5055 without significantly ( P < 0.05) decreasing the bacterial load in the lung tissue whereas augmentin takes care of bacterial proliferation. Hence, it can be used as an adjunct therapy along with antibiotics as an anti-inflammatory or an immunomodulatory agent in case of acute lung infection.

Thalidomide inhibits UVB-induced mouse keratinocyte apoptosis by both TNF-alpha-dependent and TNF-alpha-independent pathways.

Thalidomide is an anti-inflammatory pharmacologic agent that has been utilized as a therapy for a number of dermatologic diseases. Its anti-inflammatory properties have been attributed to its ability to antagonize tumor necrosis factor-alfa (TNF-alpha) production by monocytes. However, its mechanism of action in the skin is not known. To test our hypothesis that thalidomide may antagonize TNF-alpha production in the skin, we used a mouse model for acute ultraviolet-B (UVB) exposure, a known stimulus for inducing this cytokine. A single bolus dose of thalidomide (either 100 or 400 mg/kg) given immediately before UVB exposure (40-120 mJ/cm2) inhibited, in a dose-dependent manner, sunburn cell formation (i.e. keratinocyte (KC) apoptosis as defined by histologic appearance and confirmed by terminal transferase mediated biotinylated dUTP nick end labelling staining) in mouse skin biopsy specimens. However, this agent did not affect the formation of cyclobutane pyrimidine dimers, a measure of UVB-induced DNA damage, which is an early event associated with apoptosis. RNase protection assays confirmed that high (400 mg/kg), but not low (100 mg/kg), doses of thalidomide inhibited the UVB-induced increase in steady-state TNF-alpha mRNA. Additionally, our in vitro data using neonatal mouse KCs showed that thalidomide prevented UVB-induced cell death (JAM assay). The antiapoptotic effects of thalidomide can be reversed by the addition of exogenous recombinant mouse TNF-alpha and hence reconstituting UVB-induced programmed cell death. The inhibition of sunburn cell formation by low-dose thalidomide in the absence of TNF-alpha inhibition suggests that other, unidentified mechanisms of apoptosis inhibition are active. These data suggest that the anti-inflammatory effects of thalidomide can affect UVB injury, and may, in part, explain its action in photosensitivity diseases such as cutaneous lupus erythematosus.

Inhibition of NF-κB Activity by Thalidomide through Suppression of IκB Kinase Activity

The sedative and anti-nausea drug thalidomide, which causes birth defects in humans, has been shown to have both anti-inflammatory and anti-oncogenic properties. The anti-inflammatory effect of thalidomide is associated with suppression of cytokine expression and the anti-oncogenic effect with inhibition of angiogenesis. It is presently unclear whether the teratogenic properties of thalidomide are connected in any way to the beneficial, anti-disease characteristics of this drug. The transcription factor NF-kappaB has been shown to be a key regulator of inflammatory genes such as tumor necrosis factor-alpha and interleukin-8. Inhibition of NF-kappaB is associated with reduced inflammation in animal models, such as those for rheumatoid arthritis. We show here that thalidomide can block NF-kappaB activation through a mechanism that involves the inhibition of activity of the IkappaB kinase. Consistent with the observed inhibition of NF-kappaB, thalidomide blocked the cytokine-induced expression of NF-kappaB-regulated genes such as those encoding interleukin-8, TRAF1, and c-IAP2. These data indicate that the therapeutic potential for thalidomide may be based on its ability to block NF-kappaB activation through suppression of IkappaB kinase activity.

Thalidomide enhances superoxide anion release from human polymorphonuclear and mononuclear leukocytes.

The effect of thalidomide on the function of human polymorphonuclear leukocytes (PMNs) and blood monocytes was tested in vitro. The chemotactic and spontaneous migration was not affected by thalidomide between 0.001 and 0.1 mg/ml. PMN oxygen consumption was not changed after pre-incubation with thalidomide. However, superoxide anion release upon stimulation of the cells with phorbol-myristate-acetate or the chemotactic tripeptide N-f-Methionyl-Leucyl-Phenylalanine was enhanced in a dose-dependent manner after pre-incubation with thalidomide. Both PMNs and monocytes were influenced. Leukocytes from two patients with chronic granulomatous disease (defective in oxidative burst response) remained unable to produce superoxide anion after pre-incubation with thalidomide. Thus, we suggest that thalidomide primes the phagocytes to respond with an enhanced superoxide anion release upon stimulation. These findings do not explain the anti-inflammatory effect of thalidomide but could have relevance in conditions with quantitative defects in phagocyte oxidative responsiveness.