Parkinsonism Attenuation by Antihistamines via Downregulating the Oxidative Stress, Histamine, and Inflammation

Abstract

Parkinson disease (PD) is a neurodegenerative disorder of the motor activity of the brain, regulated by dopaminergic neurons of substantia nigra, resulting in an increased density of histaminergic fibers. This study was aimed to evaluate the effects of H1 antagonist’s ebastine and levocetirizine in PD per se and in combination. Animals were divided into 9 groups ( n = 10). Group 1 received carboxymethyl cellulose CMC (1 mL/kg). Group II was treated with haloperidol (1 mg/kg) (diseased group). Group III was treated with levodopa/carbidopa (levo 20 mg/kg). Groups IV and V were treated with ebastine at dose levels of 2 and 4 mg/kg, respectively. Groups VI and VII were treated with levocetirizine at dose levels of 0.5 and 1 mg/kg, respectively. Group VIII was treated with ebastine (4 mg/kg) + levo (20 mg/kg) in combination. Group IX was treated with levocetirizine (1 mg/kg) + levo (20 mg/kg). PD was induced with haloperidol (1 mg/kg iv, once daily for 23 days) for a duration of 30 min. Behavioral tests like rotarod, block and triple horizontal bars, actophotometer, and open field were performed. Biochemical markers of oxidative stress, i.e., SOD, CAT, GSH, MDA, dopamine, serotonin, and nor-adrenaline and nitrite, were determined. Histamine, mRNA expression of α-synuclein, and TNF-α level in the serum and brain of mice were analyzed. Endogenous biochemical markers were increased except mRNA expression of α-synuclein, which was reduced. In combination therapy with the standard drug, ebastine (4 mg/kg) significantly improved the cataleptic state and dopamine levels, but no significant difference in the renal and liver functioning tests was observed. This study concluded that ebastine (4 mg/kg) might work in the treatment of PD as it improves the cataleptic state in haloperidol-induced catalepsy.

Literature-Based Discovery Predicts Antihistamines Are a Promising Repurposed Adjuvant Therapy for Parkinson’s Disease

“…In fact, one study suggested that, when used with levodopa, ebastine and levocetirizine each significantly improved PD-like side effects induced in mouse models. The benefit was further amplified when the treatments were administered in combination with levodopa, and the mRNA expression of PD markers was significantly lowered [17]. These preclinical findings show the potential value of co-administering antihistamines with levodopa to better manage the motor hallmarks of clinical PD.…”

“…The reinstatement of a proper balance between dopamine and acetylcholine is another possible mechanism of action for ebastine and levocetirizine to improve PD. Ebastine and levocetirizine have been found to decrease acetylcholine levels in mouse models [17]. The alleviation of neurotransmitter imbalances indicates the potential utility of antihistamines as a repurposed drug or adjuvant therapy for PD.…”

“…Ebastine was one of the highly ranked repurposed drugs predicted by cross-domain text mining. Ebastine induces a dose-dependent increase in the activity of antioxidant enzymes like SOD, CAT, and GSH as well as a decrease in accompanying biomarkers of oxidative stress like MDA and nitrite [17]. Additionally, levocetirizine, another highly ranked cross-domain text-mining result, similarly fosters a significant increase in the activity of SOD [30].…”

Assessing the Safety and Therapeutic Efficacy of Cannabidiol Lipid Nanoparticles in Alleviating Metabolic and Memory Impairments and Hippocampal Histopathological Changes in Diabetic Parkinson’s Rats

“…Interestingly, the treatment with CBD-LNP resulted in a significant decrease in latency on the bar test, suggesting an ameliorative effect on muscular rigidity and muscle stiffness-like symptoms. Likewise, levodopa treatment demonstrated efficacy in alleviating catalepsy, supporting its role as a positive control [ 66 , 67 ].…”

Astemizole, a Second-Generation Histamine H1-Receptor Antagonist, Did Not Attenuate the Aggregation Process of α-Synuclein In Vitro

“…The favorable effects of the antihistamine astemizole seen in several translational PD studies might be due to mechanisms other than the inhibition of amyloid aggregation. Previous translational studies have indicated that the symptomatic attenuation of Parkinsonism symptoms by histamine H1-receptor antagonists such as ebastine and levocetirizine may be related to the downregulation of oxidative stress and anti-inflammatory effects [ 30 , 31 ]. A previous in vitro study examined whether astemizole induces autophagy in PK1 neuroblastoma cells and monitored the conversion of the cytosolic protein LC3-I into the autophagosome-bound form LC3-II.…”