Drug and Class

Major outcomes

Detailed Methodology

Rosiglitazone,

a selective peroxisome proliferator-activated receptor γ (PPAR-γ) agonist

(Glitazone)

Rosiglitazone as an inhaled formulation, for the treatment of PAH, it has the potential to dilate pulmonary arteries and to attenuate arterial remodeling in PAH. Rosiglitazone can be repurposed as inhaled formulation for the treatment of PAH. The optimized formulation, given via the pulmonary route, produced pulmonary selective vasodilation in PAH animals, but oral rosiglitazone had no effect in pulmonary hemodynamics. Rosiglitazone ameliorates the pathogenesis of PAH by balancing the molecular regulators involved in the vasoconstriction and vasodilation of human pulmonary arterial smooth muscle cells.

The authors have tested this conjecture by preparing and optimizing poly(lactic-co-glycolic) acid (PLGA) based particles of rosiglitazone, assessing the drug particles for pulmonary absorption, investigating the efficacy of the plain versus particulate drug formulation in improving the respiratory hemodynamics in PAH animals, and finally studying the effect of the drug in regulating the molecular markers associated with PAH pathogenesis. The optimized particles were slightly porous and spherical, and released 87.9% ± 6.7% of the drug in 24 h. The elimination half-life of the drug formulated in PLGA particles was 2.5-fold greater than that of the plain drug administered via the same route at the same dose [1].

Sitagliptin

Dipeptidyl peptidase -4

Inhibitor

(DPP-4 inhibitor, gliptin).

Sitagliptin rescues memory deficits in Parkinsonian rats via upregulating BDNF to prevent neuron and dendritic spine loss. The study showed that sitagliptin improved memory deficits in PD rats. Meanwhile, the expression level of BDNF and tyrosine hydroxylase (TH) was upregulated, and the density of dendritic spine was increased by sitagliptin administration. Moreover, K252a administration blocked the positive effects of sitagliptin on memory in PD rats. Sitagliptin rescued the memory deficits, which was achieved by upregulating BDNF to prevent neuronal death and dendritic spine loss. Sitagliptin might be a promising potential drug for PD treatment in the future.

First, the memory of rats in each group was evaluated with the Morris water maze (MWM) test and the passive avoidance test. Then, both brain-derived neurotrophic factor (BDNF) protein and mRNA levels were detected by ELISA and qPCR assays, respectively. Then, rapid Golgi impregnation was used to observe the density of dendritic spines in the hippocampal CA1 area. Finally, k252a, an antagonist of Trk receptors, was used to block the binding of BDNF with its receptors, and the effects of sitagliptin on PD improvement were detected [2].

Linagliptin

Dipeptidyl peptidase -4

Inhibitor

(DPP-4 inhibitor, gliptin).

Linagliptin potentiates the effect of L-dopa on the behavioural, biochemical and immunohistochemical changes in experimentally-induced Parkinsonism. Role of toll-like receptor 4, TGF-β1, NF-κB and glucagon-like peptide 1 was investigated. The combination of L-dopa/Carbidopa and linagliptin in a dose-dependent manner resulted in significant improvement of the behavioural changes, striatal dopamine, antioxidant parameters, Nrf2/HO-1 content, GLP-1, ATP and mitochondrial complex I activity with significant decrease in striatal RAGE, TGF-β1, TNF-α, IL-10, TLR4 and alleviated the immunohistochemical changes better than the groups that received either L-dopa/Carbidopa or linagliptin alone. The combination of L-dopa/Carbidopa and linagliptin might represent a promising therapeutic modality for management of parkinsonism.

Eighty Balb/c mice were divided into 8 equal groups: Control; MPTP; MPTP + L-dopa/Carbidopa; MPTP + linagliptin 3 mg/kg/day; MPTP + linagliptin 10 mg/kg/day; MPTP + Carboxymethyl cellulose; MPTP + L-dopa/Carbidopa + linagliptin 3 mg/kg/day and MPTP + L-dopa/Carbidopa + linagliptin 10 mg/kg/day. Striatal dopamine, tumor necrosis factor alpha (TNF-α), interleukin 10 (IL-10), transforming growth factor beta 1 (TGF-β1), toll-like receptor 4 (TLR4), antioxidant enzymes, adenosine triphosphate (ATP), glucagon-like peptide-1 (GLP-1), receptors of advanced glycation end products (RAGE), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase-1 (HO-1), mitochondrial complex I activity, catalepsy and total swim scores were measured. Also, the substantia nigra was subjected to immunohistochemical examination [3].

Pioglitazone, a selective peroxisome proliferator-activated receptor γ (PPAR-γ) agonist

(Glitazone)

Pioglitazone reduces mortality, prevents depressive-like behavior, and impacts hippocampal neurogenesis in the 6-OHDA model of Parkinson's disease in rats. It has been shown to exert anti-inflammatory and antidepressant effects and modulate neural plasticity in several neurodegenerative disorders. These results indicate that pioglitazone exerts neuroprotective effects by facilitating hippocampal neurogenesis in 6-OHDA-lesioned rats, which might contribute to its antidepressant-like effect.

The present study investigated the effects of pioglitazone on depressive phenotypes and adult hippocampal neurogenesis in a rat model of PD that was induced by bilateral 6-hydroxydopamine (6-OHDA) infusions in the substantia nigra pars compact (SNpc). Rats with SNpc and ventral tegmental area (VTA) neurodegeneration exhibited despair-like behavior, concomitant with persistent microglial activation in the hippocampus. Pioglitazone reduced the rate of mortality and attenuated microglial activation in the early phase of 6-OHDA-induced nigral lesions. Pioglitazone exerted antidepressant-like effects and increased the survival of neurons in the hippocampus in rats with nigral lesions [4].

Linagliptin

Dipeptidyl peptidase -4

Inhibitor

(DPP-4 inhibitor, gliptin).

Structural re-positioning, in silico molecular modelling, oxidative degradation, and biological screening of linagliptin as adenosine 3 receptor (ADORA3) modulators targeting hepatocellular carcinoma was reported.

Both of LIN and DEG showed inhibitory profile against hepatocellular carcinoma cell lines with induction of apoptosis at G2/M phase with increase in caspase-3 levels, accompanied by a down-regulation in gene and protein expression levels of ADORA3 with a subsequent increase in cAMP. Quantitative in vitro assessment of LIN binding affinity against ADORA3 was also performed to exhibit inhibitory profile at Ki of 37.7 nM. In silico molecular modelling showing binding affinity of LIN and DEG towards ADORA3 was conducted [5].

Omarigliptin

Dipeptidyl peptidase -4

Inhibitor

(DPP-4 inhibitor, gliptin).

Repositioning of omarigliptin as a once-weekly intranasal anti-parkinsonian agent was reported. Sitagliptin, vildagliptin, saxagliptin and linagliptin showed antioxidant and neurorestorative effects in previous studies linked to DPP-4 inhibition. Literature showed that gliptins did not cross the blood brain barrier (BBB) while omarigliptin was the first gliptin that crossed it successfully in the present work. A novel intranasal formulation was developed using sodium lauryl sulphate surfactant to solubilize the lipophilic omarigliptin with penetration enhancing and antimicrobial properties.

LC-MS/MS determination of once-weekly anti-diabetic DPP-4 inhibitors; omarigliptin and trelagliptin in plasma and brain tissue was employed after 2 h of oral administration to rats. The brain/plasma concentration ratio was used to deduce the penetration power through the BBB. Results showed that only omarigliptin crossed the BBB due to its low molecular weight and lipophilic properties suggesting its repositioning as antiparkinsonian agent. Intranasal administration showed enhanced brain/plasma ratio by 3.3 folds compared to the oral group accompanied with 2.6 folds increase in brain glucagon-like peptide-1 concentration compared to the control group [6].

Exenatide

a glucagon-like peptide-1 (GLP-1) receptor agonist.

The response of individual non-motor symptoms to an intervention may vary and thus this post hoc analysis was conducted to explore the possible effects of exenatide compared to placebo on individual non-motor symptoms. These exploratory findings will contribute to the design of future trials to confirm the extent of motor and non-motor symptom effects of exenatide in larger cohorts of patients.

Compared to placebo, patients treated with exenatide-once weekly had greater improvements in individual domains assessing mood/depression across all observer-rated outcome measures after 48 weeks including the "mood/apathy" domain of the NMSS,-3.3 points (95% CI-6.2,-0.4), p = 0.026; the "mood" score (Q1.3+Q1.4 of the MDS-UPDRS Part 1),-0.3 points (95%CI-0.6,-0.1), p = 0.034; and a trend in the MADRS total score,-1.7 points (95%CI-3.6, 0.2), p = 0.071. In addition, there was an improvement in the "emotional well-being" domain of the PDQ-39 of 5.7 points ((95%CI-11.3,-0.1), p = 0.047 though these improvements were not sustained 12 weeks after exenatide withdrawal. At 48 weeks these changes were of a magnitude that would be subjectively meaningful to patients and were not associated with changes in motor severity or other factors, suggesting exenatide may exert independent effects on mood dysfunction [7].

Indaceterol and

Canagliflozin

(sodium glucose linked transport proteins, SGLT2 Inhibitor)

Identification of clinically approved drugs indacaterol and canagliflozin for repurposing to treat epidermal growth factor tyrosine kinase inhibitor-resistant lung cancer was reported. The positive hints were revealed to be indacaterol, canagliflozin, and cis-flupenthixol, all of which were shown to induce apoptosis in NSCLC cells harboring the EGFR T790M mutation. Moreover, the combination of indacaterol with gefitinib was also found to produce synergistic anticancer effect in NSCLC cells bearing EGFR T790M. The observed synergistic effect was likely contributed by the enhanced inhibition of EGFR (epidermal growth factor tyrosine) and its downstream signaling molecules.

The authors used their free and open-source protein-ligand docking software idock to screen worldwide approved small-molecule drugs against EGFR T790M. The computationally selected drug candidates were evaluated in vitro in resistant non-small cell lung cancer (NSCLC) cell lines. The specificity of the drugs toward the mutant EGFR was demonstrated by cell-free kinase inhibition assay. The inhibition of EGFR kinase activity and its downstream signaling pathways in NSCLC cells was shown by immunoblot analysis [8].

Exenatide

a glucagon-like peptide-1 (GLP-1) agonist

Exenatide, , has been reported to ameliorate the severity of motor symptoms associated with PD. The positive results from this study replicate the benefits of exenatide demonstrated in a prior open-label trial with a smaller cohort of patients.

In this trial, exenatide, self-administered as 2 mg subcutaneous injections at once-weekly intervals for a total of 48 weeks, was associated with a modest but statistically significant reduction in the severity of motor symptoms, as determined using the Movement Disorders Society Unified PD Rating Scale (MDS–UPDRS) motor subscale (part 3). Patients in the exenatide group had an adjusted difference of −3.5 points (a lower score indicating less-severe symptoms) relative to those in the control group (P = 0.0318) when their symptoms were investigated in the practically defined off-medication state at 60 weeks after the start of treatment, which was the primary outcome measure. Comparisons of secondary outcomes, such as symptoms encompassed by MDS–UPDRS parts 1, 2, and 4, as well as 'on' part 3 scores, functional outcome measures and others, did not reveal any significant differences between the groups [9].

Glitazones

a selective peroxisome proliferator-activated receptor γ (PPAR-γ) agonist

Glitazone use was associated with reduced risk of Parkinson's disease. The objective of this study was to examine if the use of glitazone drugs is associated with a lower incidence of PD among diabetic patients. The use of glitazones is associated with a decreased risk of incident PD in populations with diabetes. Further studies are warranted to confirm and understand the role of glitazones in neurodegeneration.

The authors compared the incidence of PD between individuals with diabetes who used glitazones, with or without metformin, and individuals using only metformin in the Norwegian Prescription Database. This database contains all prescription drugs dispensed for the entire Norwegian population. We identified 94,349 metformin users and 8396 glitazone users during a 10-year period and compared the incidence of PD in the 2 groups using Cox regression survival analysis, with glitazone exposure as a time-dependent covariate. Results showed that Glitazone use was associated with a significantly lower incidence of PD compared with metformin-only use (hazard ratio, 0.72; 95% confidence interval, 0.55-0.94; P = 0.01) [10].

Exenatide

a glucagon-like peptide-1 (GLP-1) receptor agonist.

Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial was reported. It has neuroprotective effects in preclinical models of Parkinson's disease. The authors investigated whether these effects would be apparent in a clinical trial. Whether exenatide affects the underlying disease pathophysiology or simply induces long-lasting symptomatic effects is uncertain. Exenatide represents a major new avenue for investigation in Parkinson's disease, and effects on everyday symptoms should be examined in longer-term trials.

In this single-centre, randomised, double-blind, placebo-controlled trial, patients with moderate Parkinson's disease were randomly assigned (1:1) to receive subcutaneous injections of exenatide 2 mg or placebo once weekly for 48 weeks in addition to their regular medication, followed by a 12-week washout period. Eligible patients were aged 25–75 years, had idiopathic Parkinson's disease as measured by Queen Square Brain Bank criteria, were on dopaminergic treatment with wearing-off effects, and were at Hoehn and Yahr stage 2·5 or less when on treatment. Randomisation was by web-based randomisation with a two strata block design according to disease severity. Patients and investigators were masked to treatment allocation. The primary outcome was the adjusted difference in the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor subscale (part 3) in the practically defined off-medication state at 60 weeks. All efficacy analyses were based on a modified intention-to-treat principle, which included all patients who completed any post-randomisation follow-up assessments. Exenatide had positive effects on practically defined off-medication motor scores in Parkinson's disease, which were sustained beyond the period of exposure [11].

Exenatide

a glucagon-like peptide-1 (GLP-1) receptor agonist.

Neuroprotective Effects of Eexenatide in a Rotenone-Induced Rat Model of Parkinson's Disease was studied. Exenatide has been evaluated as a neuroprotective agent in multiple animal models. Malondialdehyde and tumor necrosis factor alpha levels increased in the rats with PD induced by rotenone, The apomorphine-induced rotation test scores of exenatide-treated rats were determined to be lower compared with the untreated group. Additionally, treatment with exenatide significantly reduced the loss of dopaminergic neurons in striatum. These results have shown that exenatide has neuroprotective, anti-inflammatory and antioxidant effects in a rotenone-induced rat model of PD.

Rotenone models of PD have great potential for the investigation of PD pathology and motor and nonmotor symptoms, as well as the role of gene-environment interactions in PD causation and pathogenesis. Therefore, in this study, the neurochemical, behavioral and histologic effects of exenatide on a rotenone-induced rat model of PD were examined. Eighteen adult male rats were randomly divided into the following 3 groups (n = 6): 1 group received stereotaxical infusion of dimethyl sulfoxide (vehicle, group 1) and the others received stereotaxical infusion of rotenone (groups 2 and 3). Apomorphine-induced rotation test was applied to the rats after 10 days. Thereafter, group 2 was administered isotonic saline, whereas group 3 was administered exenatide for 28 days [12].

Sitagliptin

Liraglutide

Sitagliptin

Dipeptidyl peptidase -4

Inhibitor

(DPP-4 inhibitor, gliptin).

and

Liraglutide

a glucagon-like peptide-1 (GLP-1) receptor agonist.

Sitagliptin and liraglutide reversed nigrostriatal degeneration of rodent brain in rotenone-induced Parkinson’s disease. The study investigated the possible relationship between pro-inflammatory cytokines and programmed nigral neuronal death in rotenone model of Parkinson’s disease (PD). Sitagliptin and liraglutide efficacy to inhibit the inflammatory-apoptotic degenerative process were investigated,

Sitagliptin and liraglutide represent a promising strategy to mitigate the progression of PD by their anti-inflammatory, anti-apoptotic neurotrophic and neurogenic mechanistic activities.

The experimental PD were induced in male albino rats by ten subcutaneously injections of rotenone (3 mg/kg/day, s.c). All treatment drugs were administered for 16 days after induction of Parkinson rat’s model. Sitagliptin and liraglutide were administered in three different dose levels (10–20–30 mg/kg, p.o), (25–50–100 μg/kg, s.c), respectively. Cylindrical and catalepsy tests were used to detect the optimum dose response of each drug. Sitagliptin (30 mg/kg/day, p.o) and liraglutide (50 μg/kg, s.c.) showed statistically significant (p ≤ 0.05) effect on behavioral activity. Where both doses improved the motor performance significantly in comparison with other doses in both cylindrical and catalepsy tests. Furthermore, they reversed rotenone-induced nigral neuronal loss, associated with marked decrease of pro-inflammatory cytokines: interleukin (IL)-1β, IL-6, transforming growth factor (TGF)-β1, together with a significant increase of striatal dopamine, nigral glial cell line-derived neurotrophic factor (GDNF), and tyrosine hydroxylase positive (TH+) cells. Moreover, the pro-apoptotic environment in nigrostriatal tissues was abrogated significantly, as the pro-apoptotic protein Bax decreased along with the anti-apoptotic protein Bcl-2 increased [13].

Exenatide

a glucagon-like peptide-1 (GLP-1) receptor agonist.

Exenatide is suitable for treatment of Parkinson's Disease

Randomized, double-blind, placebo controlled trial was designed, patients with moderate stage Parkinson's disease treated with once-weekly subcutaneous injections of exenatide 2mg (Bydureon) for 48 weeks, had a 3.5-point advantage over the placebo group in the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor subscale (Part 3) in the practically defined OFF medication state, 12 weeks after cessation of the trial drug [14].

a glucagon-like peptide-1 (GLP-1) receptor agonist.

A novel GLP-1/GIP dual agonist is more effective than liraglutide in reducing inflammation and enhancing GDNF release in the MPTP mouse model of Parkinson's disease. Combination of GLP-1 and GIP receptor activation is superior to single GLP-1 receptor activation alone. Therefore, new dual agonists may be a promising treatment for PD. The GLP-1 receptor agonist exendin-4 has already shown disease modifying effects in clinical trials in PD patients.

Dual GLP-1/GIP receptor agonists have been developed. The authors therefore tested the novel dual agonist DA3-CH in comparison with the best GLP-1 analogue currently on the market, liraglutide (both drugs 25 nmol/kg ip once-daily for 7 days) in the MPTP mouse model of PD (25 mg/kg ip once-daily for 7 days). In the Rotarod and grip strength assessment, DA3-CH was superior to liraglutide in reversing the MPTP–induced motor impairment. Dopamine synthesis as indicated by levels of tyrosine hydroxylase was much reduced by MPTP in the substantia nigra and striatum, and DA3-CH reversed this while liragutide only partially reversed this. The chronic inflammation response as shown in increased levels of activated microglia and astrocytes was reduced by both drugs. Importantly, expression levels of the neuroprotective growth factor Glial Derived Neurotrophic Factor (GDNF) was much enhanced by both DA3-CH and liragutide [15].

Liraglutide

a glucagon-like peptide-1 (GLP-1) receptor agonist.

Characterization of liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, in rat partial and full nigral 6-hydroxydopamine lesion models of Parkinson's disease. liraglutide showed no neuroprotective effects in the context of moderate or substantial midbrain dopaminergic neuronal loss and associated functional motor deficits in the rat 6-OHDA lesion model of PD.

The authors characterized the effect of a long-acting GLP-1 receptor agonist, liraglutide (500 μg/kg/day, s.c.) in the context of a partial or advanced (full) 6-OHDA induced nigral lesion in the rat. Rats received a low (3 μg, partial lesion) or high (13.5 μg, full lesion) 6-OHDA dose stereotaxically injected into the right medial forebrain bundle (n=17-20 rats per experimental group). Six weeks after induction of a partial nigral dopaminergic lesion, vehicle or liraglutide was administered for four weeks. In the full lesion model, vehicle dosing or liraglutide treatment was applied for a total of six weeks starting three weeks pre-lesion, or administered for three weeks starting on the lesion day. Quantitative stereology was applied to assess the total number of midbrain tyrosine hydroxylase (TH) positive dopaminergic neurons. As compared to vehicle controls, liraglutide had no effect on the rotational responsiveness to d-amphetamine or apomorphine, respectively. In correspondence, while numbers of TH-positive nigral neurons were significantly reduced in the lesion side (partial lesion ≈55%; full lesion ≈90%) liraglutide administration had no influence dopaminergic neuronal loss in either PD model setting [16].

Pioglitazone

a selective peroxisome proliferator-activated receptor γ (PPAR-γ) agonist

(Glitazone)

Pioglitazone ameliorates the phenotype of a novel Parkinson's disease mouse model by reducing neuro-inflammation. By triggering a mitochondrial Complex IV defect in dopaminergic neurons, the authors created a new mouse model resembling the late stages of PD with massive degeneration of dopaminergic neurons and striatal dopamine depletion. The motor phenotypes were improved by Pioglitazone treatment, suggesting that targetable secondary pathways can influence the development of certain forms of PD.

In order to analyze the role of Complex IV in PD, the authors knocked out Cox10 (essential for the maturation of COXI, a catalytic subunit of Complex IV) in dopaminergic neurons. The authors also tested whether the resulting phenotype was improved by stimulating the PPAR-γ pathway. Results: Cox10/DAT-cre mice showed decreased numbers of TH+ and DAT+ cells in the substantia nigra, early striatal dopamine depletion, motor defects reversible with L-DOPA treatment and hypersensitivity to L-DOPA with hyperkinetic behavior. We found that chronic pioglitazone (PPAR-γ agonist) treatment ameliorated the motor phenotype in Cox10/DAT-cre mice. Although neither mitochondrial function nor the number of dopaminergic neurons was improved, neuroinflammation in the midbrain and the striatum was decreased [17].

Rosiglitazone

a selective peroxisome proliferator-activated receptor γ (PPAR-γ) agonist

(Glitazone)

The retina as an early biomarker of neurodegeneration in a rotenone-induced model of Parkinson's disease. Evidence for a neuroprotective effect of rosiglitazone in the eye and brain was reported. The study showed that rosiglitazone can efficiently protect retinal neurons from the rotenone insult, and that systemic administration of liposome-encapsulated rosiglitazone has an enhanced neuroprotective effect on the retina and CNS (Central Nervous System). These findings suggest that retinal changes may be a good surrogate biomarker for PD, which may be used to assess new treatments both experimentally and clinically.

A rotenone-induced rodent model of PD was employed to investigate retinal manifestations in PD and their usefulness in assessing the efficacy of a novel therapeutic intervention with a liposomal formulation of the PPAR-γ (Peroxisome proliferator-activated receptor gamma) agonist rosiglitazone. Retinal assessment was performed using longitudinal in vivo imaging with DARC (detection of apoptosing retinal cells) and OCT (optical coherence tomography) technologies and revealed increased RGCs (Retinal Ganglion Cells) apoptosis and a transient swelling of the retinal layers at day 20 of the rotenone insult. Follow-up of this model demonstrated characteristic histological neurodegenerative changes in the substantia nigra and striatum by day 60, suggesting that retinal changes precede the "traditional" pathological manifestations of PD. The therapeutic effect of systemic administration of different formulations of rosiglitazone was then evaluated, both in the retina and the brain. Of all treatment regimen tested, sustained release administration of liposome-encapsulated rosiglitazone proved to be the most potent therapeutic strategy, as evidenced by its significant neuroprotective effect on retinal neurons at day 20, and on nigrostriatal neurons at day 60, provided convincing evidence for its potential as a treatment for PD. Our results demonstrate significant retinal changes occurring in this model of PD [18].

Pioglitazone

a selective peroxisome proliferator-activated receptor γ (PPAR-γ) agonist

(Glitazone)

Peripheral Biomarkers of Parkinson's disease progression and pioglitazone Effects, it recently failed to show promise as a disease-modifying agent in a 44-week phase 2 placebo-controlled study in 210 Parkinson's disease (PD) subjects. Pioglitazone did not significantly alter biomarker levels. Other agents that more effectively target these mechanisms remain of potential interest as disease modifying therapies in PD.

The authors analyzed peripheral biomarkers, including leukocyte PGC-1α and target gene expression, plasma interleukin 6 (IL-6) as a marker of inflammation, and urine 8-hydroxydeoxyguanosine (8OHdG) as a marker of oxidative DNA damage. Baseline or changes from baseline in biomarker levels were not associated with the rate of progression of PD [19].