Piracetam and Piracetam-Like Drugs

Abstract

There is an increasing interest in nootropic drugs for the treatment of CNS disorders. Since the last meta-analysis of the clinical efficacy of piracetam, more information has accumulated. The primary objective of this systematic survey is to evaluate the clinical outcomes as well as the scientific literature relating to the pharmacology, pharmacokinetics/pharmacodynamics, mechanism of action, dosing, toxicology and adverse effects of marketed and investigational drugs. The major focus of the literature search was on articles demonstrating evidence-based clinical investigations during the past 10 years for the following therapeutic categories of CNS disorders: (i) cognition/memory; (ii) epilepsy and seizure; (iii) neurodegenerative diseases; (iv) stroke/ischaemia; and (v) stress and anxiety. In this article, piracetam-like compounds are divided into three subgroups based on their chemical structures, known efficacy and intended clinical uses. Subgroup 1 drugs include piracetam, oxiracetam, aniracetam, pramiracetam and phenylpiracetam, which have been used in humans and some of which are available as dietary supplements. Of these, oxiracetam and aniracetam are no longer in clinical use. Pramiracetam reportedly improved cognitive deficits associated with traumatic brain injuries. Although piracetam exhibited no long-term benefits for the treatment of mild cognitive impairments, recent studies demonstrated its neuroprotective effect when used during coronary bypass surgery. It was also effective in the treatment of cognitive disorders of cerebrovascular and traumatic origins; however, its overall effect on lowering depression and anxiety was higher than improving memory. As add-on therapy, it appears to benefit individuals with myoclonus epilepsy and tardive dyskinesia. Phenylpiracetam is more potent than piracetam and is used for a wider range of indications. In combination with a vasodilator drug, piracetam appeared to have an additive beneficial effect on various cognitive disabilities. Subgroup 2 drugs include levetiracetam, seletracetam and brivaracetam, which demonstrate antiepileptic activity, although their cognitive effects are unclear. Subgroup 3 includes piracetam derivatives with unknown clinical efficacies, and of these nefiracetam failed to improve cognition in post-stroke patients and rolipram is currently in clinical trials as an antidepressant. The remaining compounds of this subgroup are at various preclinical stages of research. The modes of action of piracetam and most of its derivatives remain an enigma. Differential effects on subtypes of glutamate receptors, but not the GABAergic actions, have been implicated. Piracetam seems to activate calcium influx into neuronal cells; however, this function is questionable in the light of findings that a persistent calcium inflow may have deleterious impact on neuronal cells. Although subgroup 2 compounds act via binding to another neuronal receptor (synaptic vesicle 2A), some of the subgroup 3 compounds, such as nefiracetam, are similar to those of subgr...

Steroids Impact on Myelin Repair, Neurogenesis and Visual Pathway in Multiple Sclerosis: Preclinical Perspectives

“…"EAE is mainly a lymphocyte driven model, which makes it difficult to distinguish between direct effects of corticosteroids and indirect effect as a result of corticosteroid immunomodulation" [24]. [37], from the mean numerical fold changes after treatments with test agents relative to the base, controls/placebo, significant at ≤0.05 level EAE = experimental autoimmune encephalomyelitis; ERG = electroretinograms; FGF-2 = fibroblasts growth factor 2, known to promote OPC proliferation; GRα = glucocorticoid receptor alpha; IGF-1 = insulin-like growth factor-1, known to promote OPC maturation; IP = intraperitoneal injection; MAPK = mitogen activated protein kinase-2 phosphorylation; MBP = myelin basic protein; MOG = myelin oligodendrocyte glycoprotein; PDGFαα = platelet-derived growth factor-αα, promotes OPC proliferation; PLP = proteolipid protein; OPC = oligodendrocyte progenitor cells; RGC = retinal ganglion cell; VEP = visual evoked potential Second, recent experimental studies indicate that loss of oligodendrocytes and neurons begins in the earliest stages of the disease, and the disease progression is not associated with blood-driven inflammatory cells [52]. Other demyelinating disease models such as cuprizone-treated mice [52,53] and lysophosphatidyl choline [54] have been largely excluded in preclinical and translational studies involving GCs -probably because these animals which lack overt inflammations are unreasonably deemed inapposite model.…”

“…Axonal loss/dysfunction can occur because of a variety of nonviral causes: most notably, neurotoxins and associated downstream or intermediary products, including free radicals/oxidative damage, risk genes, and an array of other predisposing elements such as channel abnormalities/calcium elevations-all of which can lead to destruction of neurons [37][38][39] and contribute to lesions pathogenesis in multiple sclerosis [40][41][42]. Certain risk factors may additionally involve mutated myelin proteins such as proteolipid protein (PLP) with altered biochemical characteristics [43] and/or dysmyelination (reduced myelination) not demyelination, as demonstrated in murine systems in vivo [36,44].…”

Procognitive Compounds Promote Neurite Outgrowth

“…To gain better understanding of the possible effects of drugs targeted for Alzheimer's disease on cellular plasticity and to directly compare their efficacy, we selected examples of AChE inhibitors [4], NMDA receptor antagonists [5,6], sigma 1 receptor ligands [7], antioxidants [8,9,10], synaptic vesicle 2A (SV2A) ligands [11,12,13] and β-secretase 1 (BACE1) inhibitors [14,15]. We examined the effect of these compounds on primary cortical neurons to directly compare their ability to modulate neurite plasticity.…”

Modulation of Neurotransmission by a Specified Oregano Extract Alters Brain Electrical Potentials Indicative of Antidepressant-Like and Neuroprotective Activities

“…Electropharmacogram recordings in rats may reveal information regarding neurotransmitter activity and a possible clinical indication in humans [11,12].…”