The Sleep-Modulating Peptide Orexin-B Protects Midbrain Dopamine Neurons from Degeneration, Alone or in Cooperation with Nicotine

Abstract

To determine whether orexinergic hypothalamic peptides can influence the survival of brainstem dopamine (DA) neurons, we used a model system of rat midbrain cultures in which DA neurons degenerate spontaneously and progressively as they mature. We established that orexin (OX)-B provides partial but significant protection to spontaneously dying DA neurons, whereas the homologous peptide OXA has only marginal effects. Importantly, DA neurons rescued by OXB accumulated DA efficiently by active transport, suggesting that they were functional. G-proteincoupled OX1 and OX2 receptors were both present on DA neurons, but the protective effect of OXB was attributable solely to OX2 receptors; a selective inhibitor of this receptor subtype,amino]-N-(3-pyridinylmethyl)-acetamide (EMPA), suppressed this effect, whereas a selective agonist, [Ala 11 , ]OXB, reproduced it. Survival promotion by OXB required intracellular calcium mobilization via inositol-1,4,5-triphosphate and ryanodine receptors. Nicotine, a well known neuroprotective molecule for DA neurons, improved OXB-mediated rescue through the activation of a-bungarotoxin-sensitive (presumably a7) nicotinic receptors, although nicotine had no effect on its own. Altogether, our data suggest that the loss of hypothalamic orexinergic neurons that occurs in Parkinson's disease might confer an increased vulnerability to midbrain DA neurons in this disorder.

Converging roles of ion channels, calcium, metabolic stress, and activity pattern of Substantia nigra dopaminergic neurons in health and Parkinson's disease

“…A number of studies indicate that the maintained activity of SN DA neurons is not only crucial for dopamine release and fulfillment of their physiological functions but also for their maintenance and survival during development and adulthood (Michel et al 2007(Michel et al , 2013Toulorge et al 2010Toulorge et al , 2011Dragicevic et al 2015;Guerreiro et al 2015;Wang et al 2015). In accordance with the classical 'use it or lose it' principle of neuronal plasticity and neuronal loss (Swaab et al 2002;Coyle 2003;Coulson et al 2008;Valenzuela et al 2012), reduced activity of SN DA neurons seems to facilitate their degeneration in vivo and in vitro (Salthun-Lassalle et al 2004;Liss et al 2005;Janezic et al 2013).…”

“…), and survival of cultured SN DA neurons is stimulated by modulating Ca 2+ release from the ER (Guerreiro et al . ), while MPTP can induce mitochondrial as well as ER stress in DA neurons (Selvaraj et al . ).…”

“…Mitochondria take up Ca 2+ directly via a mitochondrial Ca 2+ uniporter mCU, or a mitochondrial Ca 2+ /H + exchanger Letm1 (Baughman et al 2011;De Stefani et al 2011;Waldeck-Weiermair et al 2011), or indirectly via the ER-mitochondria pathway (Rizzuto et al 2009;Drago et al 2011;Bakowski et al 2012). This pathway is involved in defining SN DA vulnerability and in PD Guardia-Laguarta et al 2015), and survival of cultured SN DA neurons is stimulated by modulating Ca 2+ release from the ER (Guerreiro et al 2015), while MPTP can induce mitochondrial as well as ER stress in DA neurons (Selvaraj et al 2012).…”

Intranasal gene delivery for treating Parkinson’s disease: overcoming the blood–brain barrier

“…In support of this, orexin-A protected against neurotoxin-induced neuronal loss in a cell culture model of PD by inducing expression of HIF-1a [98], a pro-survival transcription factor. In addition, both orexin-A and -B receptors are co-localized on SN dopamine neurons, although orexin-B receptor stimulation was more effective in delaying degeneration of dopamine neurons in rat ventral midbrain cultures than orexin-A receptor activation [99]. Although there have been no tests of intranasal orexin-A or -B in an in vivo model of PD, such an approach, or an intranasal orexin gene therapy, may provide a means to both correct the sleep disorder and slow PD progression.…”

intranasal GDNF gene therapy approach for treating Parkinson's disease

“…In support of this, orexin--A protected against neurotoxin--induced neuronal loss in a cell culture model of PD by inducing expression of HIF--1a 195 , a pro--survival transcription factor. In addition, both orexin--A and --B receptors are co--localized on SN dopamine neurons, although orexin--B receptor stimulation was more effective in delaying degeneration of dopamine neurons in rat ventral midbrain cultures than orexin--A receptor activation 196 . Although there have been no 52 tests of intranasal orexin--A or --B in an in vivo model of PD, such an approach, or an intranasal orexin gene therapy, may provide a means to both correct the sleep disorder and slow PD progression.…”