‘Rejuvenation’ protects neurons in mouse models of Parkinson’s disease

Abstract

Why dopamine-containing neurons of the brain's substantia nigra pars compacta die in Parkinson's disease has been an enduring mystery. Our studies suggest that the unusual reliance of these neurons on L-type Ca(v)1.3 Ca2+ channels to drive their maintained, rhythmic pacemaking renders them vulnerable to stressors thought to contribute to disease progression. The reliance on these channels increases with age, as juvenile dopamine-containing neurons in the substantia nigra pars compacta use pacemaking mechanisms common to neurons not affected in Parkinson's disease. These mechanisms remain latent in adulthood, and blocking Ca(v)1.3 Ca2+ channels in adult neurons induces a reversion to the juvenile form of pacemaking. Such blocking ('rejuvenation') protects these neurons in both in vitro and in vivo models of Parkinson's disease, pointing to a new strategy that could slow or stop the progression of the disease.

L-type channel inhibition by CB1 cannabinoid receptors is mediated by PTX-sensitive G proteins and cAMP/PKA in GT1-7 hypothalamic neurons

“…As LTCCs are mainly expressed in the soma and proximal dendrites of neurons and abundantly in neuroendocrine cells, their inhibition by CB1R most likely will alter somatic activities and hormone release. For instance, LTCCs activating at subthreshold potentials are expressed in midbrain dopaminergic neurons of substantia nigra [57] and hypothalamic suprachiasmatic nucleus neurons [58], which also express high densities of CB1R [59]. LTCCs regulate the shape of action potentials and the frequency of spontaneous firing [60], thus an effective up-or down-modulation of these channels by CB1R activation or deactivation can cause drastic changes to neuronal firing, neurotransmitter release and brain functions control.…”

Modeling PD pathogenesis in mice: Advantages of a chronic MPTP protocol

“…One week after treatment, mice were tested on the grid and, 24 hours later, euthanized and TH-immunoreacted so that Nissl-counterstained neurons in the SNpc could be counted. Isradipine significantly improved performance compared to mice implanted with placebo and, although MPTP/p-treated mice with isradipine lost significantly more SNpc neurons than those treated with vehicle, isradipine attenuated the loss compared to MPTP/ptreated, placebo-implanted mice (Table 1 [ 3]). Protection was not due to isradipine affecting MPTP metabolism, because brain 1-methyl-4-phenylpyridinium ion (MPP+) levels did not differ between toxin-treated groups [3].…”

“…Control mice are injected with vehicle (saline or probenecid) in the same volume and on the same schedule. Three days before treatment, and each week thereafter, mice are tested for coordination and rigidity using the grid test [1,3,5]. Briefly, mice are placed in the center of a wire mesh grid, which is then rotated 180 degrees to suspend them upside down.…”

“…A model that shows great promise, particularly in its progressive nature, involves the administration of MPTP and an adjuvant, probenecid (MPTP/p), that blocks the rapid clearance of the toxin and its metabolites [2]. Chronic MPTP/p treatment produces many of the pathological hallmarks and motor deficits of PD, making it an excellent choice for studies of pathogenesis, for testing neuroprotective therapies and developing biomarkers to detect the disease presymptomatically [3,4]. This review covers the key features of this model and discusses its applicability to neuroprotective strategies.…”

A novel design of a Phase III trial of isradipine in early Parkinson disease (STEADY‐PD III)

“…Isradipine was shown to be neuroprotective in in vitro and in vivo models of parkinsonism 9, 10. The mechanism of neuroprotection is linked to selective vulnerability of substantia nigra pars compacta neurons that preferentially express L‐type calcium channels.…”