Methamphetamine- and trauma-induced brain injuries: comparative cellular and molecular neurobiological substrates

Abstract

The use of methamphetamine (METH) is a growing public health problem, because its abuse is associated with long-term biochemical and structural effects on the human brain. Neurodegeneration is often observed in humans, because of mechanical injuries (e.g., traumatic brain injury [TBI]) and ischemic damage (strokes). In this review, we discuss recent findings documenting the fact that the psychostimulant drug METH can cause neuronal damage in several brain regions. The accumulated evidence from our laboratories and those of other investigators indicates that acute administration of METH leads to activation of calpain and caspase proteolytic systems. These systems are also involved in causing neuronal damage secondary to traumatic and ischemic brain injuries. Protease activation is accompanied by proteolysis of endogenous neuronal structural proteins (alphaII-spectrin protein and microtubule-associated protein-tau), evidenced by the appearance of their breakdown products after these injuries. When taken together, these observations suggest that METH exposure, like TBI, can cause substantial damage to the brain by causing both apoptotic and necrotic cell death in the brains of METH addicts who use large doses of the drug during their lifetimes. Finally, because METH abuse is accompanied by functional and structural changes in the brain similar to those in TBI, METH addicts might experience greater benefit if their treatment involved greater emphasis on rehabilitation in conjunction with potential neuroprotective pharmacological agents such as calpain and caspase inhibitors similar to those used in TBI.

Figure 1

Schematic diagram showing calpain (red) and caspase-3 (blue) specific proteolysis following traumatic brain injury and METH expposure. As discussed, TBI and METH exposure will induce activation of the calpain and caspase protease system that leads to the proteolysis of different cell death proteins (PARP and DFF-4) along with structural products (Tau, αII spectrin and lamin A) which will generate signature breakdown products (BDPs) indicative of the selectivitiy of either capase (blue) or calpain (red) activation.

Figure 2

TBI/METH Exposure induces neurotoxicity via two protease-dependent cell death pathways (neural necrosis and apoptosis). The use of calpain inhibitor and caspase inhibitor can provide protection against METH-induced neurotoxicity and would ameliorate the psychiatric deficits observed.