Parkinson’s disease (PD) is the second most common progressive neurodegenerativemovement disorder, affecting about 1% of adults aged over 55 years, characterized by fourcardinal motor manifestations viz. bradykinesia, tremor, muscular rigidity and posturalinstability. Although PD is primarily a movement disorder, depression in PD (DPD) is one of themost common psychiatric symptoms that complicate the course of the illness. Patients with DPDhave more severe neurologic symptoms than those with PD and no depression, indicating anadvanced and widespread neurodegenerative process.Pathologically, PD is characterized by a preferential degeneration of neurons in theSubstantia Nigra pars compacta (SNpc), resulting in a decrease of dopamine levels in itsstriatal projections. Nigrostriatal dopaminergic denervation and oxidative stress are knownto be the main culprits in the PD. Dopamine is pivotal for normal movement because itallows information on movement to be transmitted from the SNpc to the striatum, whichthen initiates and controls the ease and balance of movement. Furthermore, strong evidencenow exists to support a role for aberrant mitochondrial form and function, as well as increasedoxidative stress, in the pathogenesis of PD.Our hypothesis is to suggest NDRI – Bupropion – as the ?rst line of treatment in PDpatients with depression. It acts via dual inhibition of norepinephrin and dopamine reuptake andis devoid of clinically signi?cant serotonergic effects or direct effect of post synaptic receptors.Dual norepinephrin and dopamine reuptake inhibition is associated with unique clinical pro?lethat compounds together anti-depressant efficacy without serotonin associated side effects.Unfortunately, Bupropion also tense with a problem of increased oxidative stress in the brain.Parkinson’s Disease mainly characterized by severe motor deficits and excitotoxicityfollowed by enhanced oxidative stress, mitochondrial dysfunction as well as Neuro-inflammationand ultimately neuronal degeneration in SNpc. beta-lactam antibiotic (Ceftriaxone) demonstratesthe neuroprotective effect along with decrease oxidative stress in MPTP-induced experimentalParkinson’s disease. Therefore, a novel compound Ceftriaxone was envisaged in our study to beused in combination with Bupropion.Thus in the present research the effect of Bupropion per se, Ceftriaxone per se and combinationBupropion with Ceftriaxone was envisaged to be studied in behavioral model of parkinsonismand its associated depression and determination of oxidative stress parameters and dopaminelevel in mice. Present study investigated the possibility of synergistic potential betweenBupropion and Ceftriaxone for ameliorating MPTP induced Parkinsonism and associateddepression in mice.MPTP was inebriated by administration of one injection of MPTP 20 mg/kg i.p. every 2hour for a total of four doses over an 8 hour period in 1 day on Day 0. Induction phase was keptfor 7 days and treatment was started from day 8th and continued till 21 st day. Syndopa100/10mg/kg, p.o. was used as control.Behavioral parameters like, catalepsy score, horizontal bar test, hang test, acceleratedrota-rod test, open field test were assessed. Depression associated with Parkinsonism disease wasevaluated using forced swim test. Biochemical estimations like TBARS, GSH, Catalase andMPO were performed to evaluate the level of oxidative stress in the brain. Lastly, histopathologywas performed using haematoxylin and eosin stain. All the statistical analysis was performed byone-way ANOVA followed by tukey’s test as post hoc analysis using Sigma Stat software, USA.A value of P < 0.05 was considered to be statistically significant.This is the first study to evaluate the effect of combination of Bupropion and Ceftriaxone inParkinsonism and associated depression in mice. Parkinsonism is mainly affected by progressiveimpairment or deterioration of neurons in an area of the brain known as the Substantia Nigra. Onthe other hand, depression is the common co-morbidity of this disease. Depression in PD ismainly due to lack of the chemical dopamine, which causes the symptoms of Parkinson’s, can bea trigger for depression.Therefore, in lieu of above effects Ceftriaxone was selected as one of treatment. Recentresearch highlights Ceftriaxone as neuroprotector because it protects dopaminergic neurons andameliorates neurological disorders associated with glutamate excitotoxicity. It can cross bloodbrain barrier and upregulate the functional expressions of glutamate transporter subtype 1-GLT1. Moreover, GLT1 has proved as the predominant glutamate transporter, so as to maintainconstant low level of extracellular glutamate. This prevents glutamate neurotoxicity.In addition to it, Bupropion acts via dual inhibition of norepinephrine and dopaminereuptake and is without any clinically significant serotonergic side effect. Compounds with dualnorepinephrine and dopamine reuptake inhibition is associated with unique clinical profile suchthat they are without serotonin associated side effects such as weight gain, sedation, sexualdysfunction. Several previous studies since 1984 indicated the use of Bupropion forParkinsonism induced depressed patients.So, in our study we envisaged the use of Ceftriaxone and Bupropion combination for thetreatment of Parkinsonism and associated depression respectively. We expected both the drugs tocomplement each other’s effect and our main objective was to reduce the therapeutic dose ofCeftriaxone and Bupropion for mitigating the side-effects of each other.Results from our study indicated that, Bupropion and Ceftriaxone dose dependently attenuatedall behavior abnormalities of MPTP in catalepsy score test, bar test, hang test, actophotometer,rota-rod in mice. Above pharmacological interventions also alleviate PD induced depression inFST. This is in line with previous research in which Bupropion was used as anti-Parkinsoniandrug. Ceftriaxone due to antioxidant effect which is better than Bupropion is also reported to bebeneficial in ameliorating PD. In addition to this, combination of Bupropion and Ceftriaxoneunveiled a synergistic potential compared to Bupropion per se and Ceftriaxone per se.Isobolographic analysis was done and it revealed total dose fraction of 0.49 which falls insynergistic range.The results of biochemical studies confirmed a state of increased oxidative stress in thebrain of MPTP induced mice. These observations are in line with earlier reports in whichParkinsonism and depression treatment were responsible for increasing TBARS, MPO levels anddecreasing GSH levels and CAT activity. The combined treatment of Bupropion and Ceftriaxonein proportion to the fixed ratios of equi-effective ED50 dose for each drug exhibited attenuationof oxidative stress in the brains of Parkinsonism induced depression in mice.The results obtained in the present study unveiled that Bupropion per se and Ceftriaxoneper se mitigates the behavioral abnormalities of PD in mice. Biochemical studies revealed thatboth are antioxidant, albeit Ceftriaxone is better antioxidant than Bupropion. Combination ofBupropion and Ceftriaxone revealed synergistic super-addictive effect, which significantly (P <0.05) ameliorated behavioral and biochemical abnormalities compared to vehicle control.Isobolographic analysis exhibited total dose fraction of 0.49 for the combination, which fallsunder synergistic potential. Histopathological reports also confirmed the absence of LewisBodies in all the pharmacological interventions similar to vehicle control.Ceftriaxone, which is one of the most potent antibiotics in beta lactam family, is able to passfreely via the blood brain barrier. It is documented that Ceftriaxone-mediated neuroprotectionmight relate more strongly to activation of the antioxidant defense system including Nrf2 thanthe up-regulation of GLT1. Therefore, neuroprotective effect of Ceftriaxone could be contributeddue to Nrf2. Upregulation of nigrostriatal Nrf2 antioxidant defense system, protectsdopaminergic neurons against the MPP(+)-induced toxicity. Functional GLT1 expression ofCeftriaxone attenuates oxidative stress by decreasing MPO, increasing Catalase, increasing GSHand decreasing TBARS levels. On the other hand, Bupropion acts via dual inhibition ofnorepinephrine and dopamine reuptake and reported moderately effective in the treatment ofmotor symptoms in mice associated with PD. Bupropion, due to dopamine reuptake activityincreases the level of dopamine in Substantia Nigra which can improve therapeuticallydepressive symptoms related with PD. As, dopamine metabolism and oxidative stress in thebrain are inter-linked, therefore, increased dopamine levels in brain by Bupropion in conjugationwith enhanced expression of Nrf2 antioxidant defense system along with GLT1 activity byCeftriaxone, shows synergistic super-additive potential in mitigating the symptoms of PD.