Alpha1- and Beta-norepinephrinergic receptors of dorsomedial and ventromedial hypothalamic nuclei modulate panic attack-like defensive behaviour elicited by diencephalic GABAergic neurotransmission disinhibition

Article

Author: da Silva, Juliana Almeida ; Uribe-Mariño, Andrés ; Coimbra, Norberto Cysne ; Castiblanco-Urbina, Maria Angélica ; Falconi-Sobrinho, Luiz Luciano ; Pigatto, Glauce Regina ; Ullah, Farhad

Gamma-aminobutyric acid (GABA) disinhibition in medial hypothalamus (MH) nuclei of rats elicits some defensive reactions that are considered panic attack-like behaviours. Recent evidence showed that the norepinephrine-mediated system modulates fear-related defensive behaviours organised by MH neurons at least in part via noradrenergic receptors recruitment on midbrain tegmentum. However, it is unknown whether noradrenergic receptors of the MH also modulate the panic attack-like reactions. The aim of this work was to investigate the distribution of noradrenergic receptors in MH, and the effects of either α₁-, α₂- or β-noradrenergic receptors blockade in the MH on defensive behaviours elaborated by hypothalamic nuclei. Defensive behaviours were evaluated after the microinjection of the selective GABA_A receptor antagonist bicuculline into the MH that was preceded by microinjection of either WB4101, RX821002, propranolol (α₁-, α₂- and β-noradrenergic receptor selective antagonists, respectively), or physiological saline into the MH of male Wistar rats. The α₁-, α₂- and β-noradrenergic receptors were found in neuronal perikarya of all MH nuclei, and the α₂-noradrenergic receptor were also found on glial cells mainly situated in the ventrolateral division of the ventromedial hypothalamic nucleus. The α₁- and β-noradrenergic receptors blockade in the MH decreased defensive attention and escape reactions elicited by the intra-MH microinjections of bicuculline. These findings suggest that, despite the profuse distributions of α₁-, α₂- and β-noradrenergic receptors in the MH, both α₁- and β-noradrenergic receptor- rather than α₂-noradrenergic receptor-signalling in MH are critical for the neuromodulation of panic-like behaviour.

05 Apr 2023·ACS Chemical Neuroscience

Duloxetine and Amitriptyline Reduce Neuropathic Pain by Inhibiting Primary Sensory Input to Spinal Dorsal Horn Neurons via α1- and α2-Adrenergic Receptors

Article

Author: Chen, Shao-Rui ; Chen, Hong ; Pan, Hui-Lin ; Huang, Yuying

Antidepressants, such as duloxetine and amitriptyline, are effective for treating patients with chronic neuropathic pain. Inhibiting norepinephrine and serotonin transporters at presynaptic terminals raises extracellular concentrations of norepinephrine. The α1- and α2-adrenergic receptor agonists inhibit glutamatergic input from primary afferent nerves to the spinal dorsal horn. However, the contribution of spinal α1- and α2-adrenergic receptors to the analgesic effect of antidepressants and associated synaptic plasticity remains uncertain. In this study, we showed that systemic administration of duloxetine or amitriptyline acutely reduced tactile allodynia and mechanical and thermal hyperalgesia caused by spinal nerve ligation in rats. In contrast, duloxetine or amitriptyline had no effect on nociception in sham rats. Blocking α1-adrenergic receptors with WB-4101 or α2-adrenergic receptors with yohimbine at the spinal level diminished the analgesic effect of systemically administered duloxetine and amitriptyline. Furthermore, intrathecal injection of duloxetine or amitriptyline similarly attenuated pain hypersensitivity in nerve-injured rats; the analgesic effect was abolished by intrathecal pretreatment with both WB-4101 and yohimbine. In addition, whole-cell patch-clamp recordings in spinal cord slices showed that duloxetine or amitriptyline rapidly inhibited dorsal root-evoked excitatory postsynaptic currents in dorsal horn neurons in nerve-injured rats but had no such effect in sham rats. The inhibitory effect of duloxetine and amitriptyline was abolished by the WB-4101 and yohimbine combination. Therefore, antidepressants attenuate neuropathic pain predominantly by inhibiting primary afferent input to the spinal cord via activating both α1- and α2-adrenergic receptors. This information helps the design of new strategies to improve the treatment of neuropathic pain.

27 Oct 2022·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of a Potent and Highly Selective Dipeptidyl Peptidase IV and Carbonic Anhydrase Inhibitor as “Antidiabesity” Agents Based on Repurposing and Morphing of WB-4101

Q1 · MEDICINE

Article

Author: Fumagalli, Laura ; Angeli, Andrea ; Vistoli, Giulio ; Gervasoni, Silvia ; Lammi, Carmen ; Bollati, Carlotta ; Baron, Giovanna ; Matucci, Rosanna ; Artasensi, Angelica ; Supuran, Claudiu T.

The management of patients with type 2 diabetes mellitus (T2DM) is shifting from cardio-centric to weight-centric or, even better, adipose-centric treatments. Considering the downsides of multidrug therapies and the relevance of dipeptidyl peptidase IV (DPP IV) and carbonic anhydrases (CAs II and V) in T2DM and in the weight loss, we report a new class of multitarget ligands targeting the mentioned enzymes. We started from the known α₁-AR inhibitor WB-4101, which was progressively modified through a tailored morphing strategy to optimize the potency of DPP IV and CAs while losing the adrenergic activity. The obtained compound 12 shows a satisfactory DPP IV inhibition with a good selectivity CA profile (DPP IV IC₅₀: 0.0490 μM; CA II K_i 0.2615 μM; CA VA K_i 0.0941 μM; CA VB K_i 0.0428 μM). Furthermore, its DPP IV inhibitory activity in Caco-2 and its acceptable pre-ADME/Tox profile indicate it as a lead compound in this novel class of multitarget ligands.

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Reperfusion Injury	Preclinical	JP	-	-

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