The role of the neuropeptide somatostatin on methamphetamine and glutamate-induced neurotoxicity in the striatum of mice

Abstract

A large body of evidence shows that methamphetamine (METH) causes sustained damage to the brain in animal models and human METH users. In chronic users there are indications of cognitive and motor deficits. Striatal neuropeptides are in a position to modulate the neurochemical effects of METH and consequently striatal neural damage. Somatostatin (SST) is an intrinsic striatal neuropeptide that has been shown to inhibit glutamate transmission; glutamate is integral to METH toxicity and contributes to nitric oxide (NO) synthesis. We hypothesize that SST will protect from METH by inhibition of NO synthesis and thus reducing oxidative stress. To this end, the SST analogue octreotide (OCT) was microinjected into the striatum prior to a systemic injection of METH (30 mg/kg). We then assessed 3-nitrotyrosine (3-NT), an indirect index of NO production, tyrosine hydroxylase (TH) protein levels (dopamine terminal marker) and Fluoro-Jade C positive cells (degenerating cells). The SST agonist OCT dose dependently attenuated the METH-induced accumulation of striatal 3-NT. Moreover, pretreatment with OCT effectively mitigated cell death but failed to protect dopamine terminals. Next we co-infused OCT and NMDA and measured 3-NT and Fluoro-Jade C staining. Treatment with OCT had no effect on these parameters. The data demonstrate that SST attenuates the METH-induced production of NO protecting the striatum from the METH-induced cell loss. However, SST failed to prevent the toxicity of the dopamine terminals suggesting that pre- and post-synaptic striatal damage occur via independent mechanisms.

Anti‐inflammatory and retinal protective effects of capsaicin on ischaemia‐induced injuries through the release of endogenous somatostatin

“…Our results indicated that pretreatment with the selective SST‐depleting agent cysteamine or using an SST receptor antagonist, such as c‐SOM, to some extent, reversed the effects of CAP, illustrating that the endogenous SST released into circulation played effective roles in anti‐inflammation and neuroprotection. Many studies have established that exogenous SST or synthetic analogues exert anti‐inflammatory and/or neuroprotective effects . Szolcsanyi et al.…”

“…7,9,29 Many studies have established that exogenous SST or synthetic analogues exert anti-inflammatory and/or neuroprotective effects. 11,[33][34][35][36][37] Szolcsanyi et al found for the first time that the mediator SST could release not only locally but also systemically from CAP-sensitive afferent fibres. 7,9 An electrical stimulation (20 v, 0.5 ms, 5 Hz for 5 minutes), which was fit for the activation of the C fibres, may diminish the contralateral limbs' plasma extravasation by 50%.…”

Neurotoxicity of methamphetamine and 3,4-methylenedioxymethamphetamine

“…Increases in glutamate in the striatum and hippocampus are known to correlate with increases in glutamate levels during Meth exposure. Recently, it was shown that somatostatin, which is a known inhibitor of glutamate neurotransmission, has the ability to reduce Meth-induced cell death in the striatum (Afanador et al, 2013). The decrease in the number of parvalbumin in the hippocampus of MDMA treated rats has been linked to the increases in extracellular glutamate and cyclooxygenase activity observed during MDMA exposure (Anneken et al, 2013).…”

Protection against Methamphetamine-Induced Striatal Apoptosis by Epigallocatechin Gallate (EGCG) in the Mouse Brain

“…The same population of striatal interneurons making NPY also makes the neuropeptide somatostatin [41]. Our laboratory recently reported that somatostatin also counters the damaging effects of METH protecting the striatal neurons from the METH-induced apoptosis [1]. Thus, neuropeptides represent endogenous agents expressed and utilized in the healthy striatum that modulate dopaminergic responses under physiological homeostatic conditions as well as in aberrant states involving a surfeit of dopamine such as induced by METH.…”

“…We have found that the striatal neuropeptide substance P synergizes with METH in elevating the production of nitric oxide [64] and consequently striatal injury [73]. Interestingly, two other striatal neuropeptides, somatostatin and neuropeptide Y, attenuate the METH-induced striatal production of nitric oxide [1,69]. In addition to endogenous agents such as neuropeptides, it is advantageous to identify exogenous substances that ameliorate oxidative stress and thus could be neuroprotective in the presence of METH.…”