Norharman-induced motoric impairment in mice: neurodegeneration and glial activation in substantia nigra

Abstract

The beta-carboline norharman is present in cooked food and tobacco smoke and show structural resemblance to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. C57BL/6 mice were injected subcutaneously with norharman (3 and 10 mg/kg) twice per day for five consecutive days. Eighteen hours after the last dose an increased expression of glial fibrillary acidic protein and fluoro-jade staining were demonstrated whereas the number of tyrosine hydroxylase positive cells were unchanged in the substantia nigra. Two weeks after the last treatment a decreased motor activity was observed whereas cognitive functions remained intact. In cultured PC12 cells norharman treatment induced mitochondrial dysfunction and increased the number of caspase-3 and TUNEL-positive cells. The results demonstrate that norharman induced apoptosis in cultured cells as well as early neurodegeneration, glial activation and sustained motor deficits in mice and suggest that exposure to norharman may contribute to idiopathic Parkinson's disease.

The effect of Banisteriopsis caapi (B. caapi) on the motor deficits in the MPTP‐treated common marmoset model of Parkinson's disease

“…Although there is some suggestion that some β‐carbolines can be neurotoxic (Haghdoost‐Yazdi, Hosseini, Faraji, Nahid, & Jahanihashemi, ; Ostergren, Fredriksson, & Brittebo, ; Ostergren, Lindquist, & Brittebo, ), evidence suggests that harmine is, if anything, neuroprotective with antiinflammatory and antiapoptotic activity (Liu et al, ; Zhong, Tao, & Yang, ) that could be beneficial in the chronic treatment of PD. In addition, these results in the MPTP‐treated primate provide support for the reports of the benefits of B. caapi and harmine monotherapy as a mild symptomatic treatment for early PD (Sanchez‐Ramos, ; Serrano‐Duenas et al, , ), as there was little or no evidence to show that there was any additive or synergistic action in conjunction with L‐DOPA that is indicated for mid to late stages of the disease.…”

Low and high doses of Norharmane respectively improve and impair learning and memory in streptozotocin-induced rat model of sporadic alzheimer’s disease

“…Previous studies have reported the involvement of cholinergic, dopaminergic and serotonergic systems in β-carbolines, such as HA -induced amnesia in the step-down passive avoidance test [49,53]. Furthermore, learning and memory may be impaired due to the major effects of β-carbolines on inhibition of MAOA and MAOB [54], and the elevated level of dopamine in the synaptic clefs.…”

Stimulation, protection and regeneration of dopaminergic neurons by 9-methyl-β-carboline: a new anti-Parkinson drug?

“…In addition, it was reported that CREB can be activated by phosphorylation via several protein kinases, inter alia PKA or C, which allows the recruitment of the CREB binding protein CREBBP [88][89][90]. When primary dopaminergic cultures were treated concomitantly with 9-me-BC and the PKA/C inhibitor AG18 (tyrphostin), the stimulation of dopaminergic neurons was completely inhibited, implying an important [19] 2,9-dimethyl-b-carboline CH 3 H CH 3 H Neurotoxic effects [21], activation of microglia [22] 9-methyl-b-carboline H H CH 3 H Neurostimulation, neuroprotection and neuroregeneration of dopaminergic neurons, anti-inflammatory effects [22],…”

“…BCs, especially methylated forms such as 2,9-dimethyl-b-carbolinium ion (2,9-dime-BC + ), have been shown to exert neurotoxic effects on dopaminergic neurons [20]. They decreased dopamine uptake, induced apoptosis via increased caspase 3 levels, inhibited mitochondrial complex I, enhanced formation of ROS and activated glia and microglia [21][22][23][24]. Furthermore, harman and norharman inhibited the topoisomerase in cell nuclei and thus disturbed the DNA repair after UV-or chemical-induced DNA damage [25].…”